U.S. patent application number 17/183253 was filed with the patent office on 2022-08-11 for heterocyclic compounds as pi3k-y inhibitors.
The applicant listed for this patent is Incyte Corporation. Invention is credited to Andrew W. Buesking, David M. Burns, Andrew P. Combs, Brent Douty, Nikoo Falahatpisheh, Daniel Levy, Lixin Shao, Stacey Shepard, Artem Shvartsbart, Richard B. Sparks, Eddy W. Yue.
Application Number | 20220251087 17/183253 |
Document ID | / |
Family ID | 1000005556824 |
Filed Date | 2022-08-11 |
United States Patent
Application |
20220251087 |
Kind Code |
A1 |
Buesking; Andrew W. ; et
al. |
August 11, 2022 |
HETEROCYCLIC COMPOUNDS AS PI3K-y INHIBITORS
Abstract
This application relates to compounds of Formula (I):
##STR00001## or pharmaceutically acceptable salts or stereoisomers
thereof, which are inhibitors of PI3K-.gamma. which are useful for
the treatment of disorders such as autoimmune diseases, cancer,
cardiovascular diseases, and neurodegenerative diseases.
Inventors: |
Buesking; Andrew W.;
(Wilmington, DE) ; Sparks; Richard B.;
(Wilmington, DE) ; Combs; Andrew P.; (Kennett
Square, PA) ; Douty; Brent; (Fallowfield, PA)
; Falahatpisheh; Nikoo; (Wilmington, DE) ; Shao;
Lixin; (Wilmington, DE) ; Shepard; Stacey;
(Wilmington, DE) ; Yue; Eddy W.; (Landenberg,
PA) ; Shvartsbart; Artem; (Kennett Square, PA)
; Burns; David M.; (Plymouth Meeting, PA) ; Levy;
Daniel; (Philadelphia, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Incyte Corporation |
Wilmington |
DE |
US |
|
|
Family ID: |
1000005556824 |
Appl. No.: |
17/183253 |
Filed: |
February 23, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16591017 |
Oct 2, 2019 |
10975088 |
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17183253 |
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16165390 |
Oct 19, 2018 |
10479795 |
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16591017 |
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15631417 |
Jun 23, 2017 |
10138248 |
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16165390 |
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62354509 |
Jun 24, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 487/04 20130101;
C07D 471/04 20130101; C07B 2200/13 20130101; C07D 519/00
20130101 |
International
Class: |
C07D 487/04 20060101
C07D487/04; C07D 471/04 20060101 C07D471/04; C07D 519/00 20060101
C07D519/00 |
Claims
1.-75. (canceled)
76. A compound, which is
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexa-
n-1-yl)-4-(methyl-d.sub.3)benzenesulfonamide.
77. The compound of claim 76, which is a crystalline free base.
78. A pharmaceutical composition comprising the compound of claim
76 and a pharmaceutically acceptable carrier.
79. A compound, which is
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexa-
n-1-yl)-4-(methyl-d.sub.3)benzenesulfonamide crystalline
hydrochloric acid salt.
80. A pharmaceutical composition comprising the compound of claim
79 and a pharmaceutically acceptable carrier.
81. A compound, which is
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexa-
n-1-yl)-4-(methyl-d.sub.3)benzenesulfonamide crystalline
benzenesulfonic acid salt.
82. A pharmaceutical composition comprising the compound of claim
81 and a pharmaceutically acceptable carrier.
83. A compound, which is
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(3-cyanobicyclo[1.1.1]pent-
an-1-yl)-4-methylbenzenesulfonamide.
84. A pharmaceutical composition comprising the compound of claim
83 and a pharmaceutically acceptable carrier.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 16/591,017, filed Oct. 2, 2019, which is a
continuation of U.S. patent application Ser. No. 16/165,390, filed
Oct. 19, 2018, which is a divisional of U.S. patent application
Ser. No. 15/631,417, filed Jun. 23, 2017, which claims the benefit
of U.S. Provisional Application No. 62/354,509, filed Jun. 24,
2016, the disclosure of which is incorporated herein by reference
in its entirety.
FIELD OF THE INVENTION
[0002] The present invention provides heterocyclic compounds that
modulate the activity of phosphoinositide 3-kinases-gamma
(PI3K.gamma.) and are useful in the treatment of diseases related
to the activity of PI3K.gamma. including, for example, autoimmune
diseases, cancer, cardiovascular diseases, and neurodegenerative
diseases.
BACKGROUND
[0003] The phosphoinositide 3-kinases (PI3Ks) belong to a large
family of lipid signaling kinases that phosphorylate
phosphoinositides at the D3 position of the inositol ring (Cantley,
Science, 2002, 296(5573):1655-7). PI3Ks are divided into three
classes (class I, II, and III) according to their structure,
regulation and substrate specificity. Class I PI3Ks, which include
PI3K.alpha., PI3K.beta., PI3K.gamma., and PI3K.delta., are a family
of dual specificity lipid and protein kinases that catalyze the
phosphorylation of phosphatidylinosito-4,5-bisphosphate (PIP.sub.2)
giving rise to phosphatidylinosito-3,4,5-trisphosphate (PIP.sub.3).
PIP.sub.3 functions as a second messenger that controls a number of
cellular processes, including growth, survival, adhesion and
migration. All four class I PI3K isoforms exist as heterodimers
composed of a catalytic subunit (p110) and a tightly associated
regulatory subunit that controls their expression, activation, and
subcellular localization. PI3K.alpha., PI3K.beta., and PI3K.delta.
associate with a regulatory subunit known as p85 and are activated
by growth factors and cytokines through a tyrosine kinase-dependent
mechanism (Jimenez, et al., J Biol Chem., 2002, 277(44):41556-62)
whereas PI3K.gamma. associates with two regulatory subunits (p101
and p84) and its activation is driven by the activation of
G-protein-coupled receptors (Brock, et al., J Cell Biol., 2003,
160(1):89-99). PI3K.alpha. and PI3K.beta. are ubiquitously
expressed. In contrast, PI3K.gamma. and PI3K.delta. are
predominantly expressed in leukocytes (Vanhaesebroeck, et al.,
Trends Biochem Sci., 2005, 30(4):194-204).
[0004] Expression of PI3K.gamma. is mainly restricted to
hematopoietic system, although it can be also detected at lower
level in endothelium, heart and brain. PI3K.gamma. knock-out or
kinase dead knock in mice are normal and fertile and do not present
any overt adverse phenotypes. Analysis at the cellular level
indicates that PI3K.gamma. is required for GPCR ligand-induced
PtdINs (3,4,5)P3 production, chemotaxis and respiratory burst in
neutrophils. PI3K.gamma.-null macrophages and dendritic cell
exhibit reduced migration towards various chemoattractants. T-cells
deficient in PI3K.gamma. show impaired cytokine production in
response to anti-CD3 or Con A stimulation. PI3K.gamma. working
downstream of adenosine A3A receptor is critical for sustained
degranulation of mast cells induced by FC.epsilon.RI cross-linking
with IgE. PI3K.gamma. is also essential for survival of eosinophils
(Ruckle et al., Nat. Rev. Drug Discovery, 2006, 5, 903-918)
[0005] Given its unique expression pattern and cellular functions,
the potential role of PI3K.gamma. in various autoimmune and
inflammatory disease models has been investigated with genetic and
pharmacological tools. In asthma and allergy models,
PI3K.gamma..sup.-/- mice or mice treated with PI3K.gamma. inhibitor
showed a defective capacity to mount contact hypersensitivity and
delayed-type hypersensitivity reactions. In these models,
PI3K.gamma. was shown to be important for recruitment of
neutrophils and eosinopohils to airways and degranulation of mast
cells (see e.g. Laffargue et al., Immunity, 2002, 16, 441-451;
Prete et al., The EMBO Journal, 2004, 23, 3505-3515; Pinho et al.,
L. Leukocyte Biology, 2005, 77, 800-810; Thomas et al., Eur. J.
Immunol. 2005, 35, 1283-1291; Doukas et al., J. Pharmacol. Exp
Ther. 2009, 328, 758-765).
[0006] In two different acute pancreatitis models, genetic ablation
of PI3K.gamma. significantly reduced the extent of acinar cell
injury/necrosis and neutrophil infiltration without any impact on
secretive function of isolated pancreatic acini (Lupia et al., Am.
J. Pathology, 2004, 165, 2003-2011). PI3K.gamma..sup.-/- mice were
largely protected in four different models of rheumatoid arthritis
(CIA, .alpha.-CII-IA, K/B.times.N serum transfer and TNF
transgenic) and PI3K.gamma. inhibition suppressed the progression
of joint inflammation and damage in the CIA and .alpha.-CII-IA
models (see e.g., Camps et al., Nat. Medicine, 2005, 11, 939-943;
Randis et al., Eur. J. Immunol, 2008, 38, 1215-1224; Hayer et al.,
FASB J., 2009, 4288-4298). In the MRL-lpr mouse model of human
systemic lupus erythematous, inhibition of PI3K.gamma. reduced
glomerulonephritis and prolonged life span (Barber et al., Nat.
Medicine, 2005, 9, 933-935).
[0007] There is evidence suggesting that chronic inflammation due
to infiltration by myeloid-derived cells is a key component in the
progression of neurodegeneration diseases, such as Alzheimer's
disease (AD) (Gir et al., Am. J. Physiol. Cell Physiol., 2005, 289,
C264-C276; El Khoury et al., Nat. Med., 2007, 13, 432-438). In line
with this suggestion, PI3K.gamma. inhibition was shown to attenuate
A.beta.(1-40)-induced accumulation of activated astrocytes and
microglia in the hippocampus and prevent the peptide-induced
cognitive deficits and synaptic dysfunction in a mouse model of AD
(Passos et al., Brain Behav. Immun. 2010, 24, 493-501). PI3K.gamma.
deficiency or inhibition also was shown to delay onset and
alleviate symptoms in experimental autoimmune encephalomyelitis in
mice, a mouse model of human multiple sclerosis, which is another
form of neurodegeneration disease (see e.g., Rodrigues et al., J.
Neuroimmunol. 2010, 222, 90-94; Berod et al., Euro. J. Immunol.
2011, 41, 833-844; Comerford et al., PLOS one, 2012, 7, e45095; Li
et al., Neuroscience, 2013, 253, 89-99).
[0008] Chronic inflammation has been formally recognized as one of
the hallmarks for many different types of cancers. Accordingly,
selective anti-inflammatory drugs represent a novel class of
anti-cancer therapies (Hanahan and Weinberg, Cell, 2011, 144,
646-674). Since PI3K.gamma. is reported to mediate various
inflammatory processes, its role as an immune oncology target has
also been investigated. A recent study reported that PI3K.gamma.
deficiency suppressed tumor growth in the syngeneic models of lung
cancer, pancreatic cancer and melanoma (LLC, PAN02 and B16).
PI3K.gamma. deficiency or inhibition also inhibited tumor growth in
a spontaneous breast cancer model (Schmid et al., Cancer Cell,
2011, 19, 715-727). A further study reported that PI3K.gamma.
deficiency could ameliorate inflammation and tumor growth in mice
having colitis-associated colon cancer, (Gonzalez-Garcia et al.,
Gastroenterology, 2010, 138, 1373-1384). Detailed mechanistic
analysis indicates that tumor infiltration by CD11b.sup.+ myeloid
cells can cause protumorigenic inflammation at tumor sites and
PI3K.gamma. in the myeloid cells is critical in mediating signaling
of various chemoattractants in bring the cells to the tumor (Schmid
et al., Cancer Cell, 2011, 19, 715-727). Other studies suggest that
PI3K.gamma. is also required for differentiation of naive myeloid
cells into M2 macrophges at tumor sites. M2 macrophages promote
tumor growth and progression by secreting immunosuppressive factors
such arginase 1, which depletes the tumor microenvironment of
arginine, thereby promoting T-cell death and NK cell inhibition
(Schmidt et al., Cancer Res. 2012, 72 (Suppl 1: Abstract, 411;
Kaneda et al., Cancer Res., 74 (Suppl 19: Abstact 3650)).
[0009] In addition to its potential role in promoting
protumorigenic microenvironment, PI3K.gamma. may play a direct role
in cancer cells. PI3K.gamma. is reported to be required for
signaling from the Kaposi's sarcoma-associated herpevirus encoded
vGPCR oncogene and tumor growth in a mouse model of sarcoma (Martin
et al., Cancer Cell, 2011, 19, 805-813). PI3K.gamma. was also
suggested to be required for growth of T-ALL (Subramanjam et al.,
Cancer Cell, 2012, 21, 459-472), PDAC and HCC cells (Falasca and
Maffucci, Frontiers in Physiology, 2014, 5, 1-10). Moreover, in a
survey of driver mutations in pancreatic cancer, PI3K.gamma. gene
was found to contain second highest scoring predicted driven
mutation (R839C) among the set of genes not previously identified
as a driver in pancreatic cancer (Carter et al., Cancer Biol. Ther.
2010, 10, 582-587).
[0010] Finally, PI3K.gamma. deficiency also has been reported to
offer protection to experimental animals in different
cardiovascular disease models. For examples, lack of PI3K.gamma.
would reduce angiotension-evoked smooth muscle contraction and,
therefore, protect mice from angiotension-induced hypertension
(Vecchione et al., J. Exp. Med. 2005, 201, 1217-1228). In rigorous
animal myocardial infarction models, PI3K.gamma. inhibition
provided potent cardioprotection, reducing infarct development and
preserving myocardial function (Doukas et al., Proc. Natl. Acad.
Sci. USA, 2006, 103, 19866-19871).
[0011] For these reasons, there is a need to develop new
PI3K.gamma. inhibitors that can be used for the treatment of
diseases such as cancer, autoimmune disorders, and inflammatory and
cardiac diseases. This application is directed to this need and
others.
SUMMARY
[0012] The present invention related to, inter alia, compounds of
Formula (I):
##STR00002##
or pharmaceutically acceptable salts, wherein constituent members
are defined herein.
[0013] The present invention further provides pharmaceutical
compositions comprising a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier.
[0014] The present invention further provides pharmaceutically
acceptable salt forms of the compounds of Formula (I).
[0015] The present invention further provides crystalline forms of
the compounds of Formula (I).
[0016] The present invention further provides methods of inhibiting
an activity of PI3K.gamma. kinase comprising contacting the kinase
with a compound of Formula (I), or a pharmaceutically acceptable
salt thereof.
[0017] The present invention further provides methods of treating a
disease or a disorder associated with abnormal PI3K.gamma. kinase
expression or activity in a patient by administering to a patient a
therapeutically effective amount of a compound of Formula (I), or a
pharmaceutically acceptable salt thereof.
[0018] The present invention further provides a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, for use in any
of the methods described herein.
[0019] The present invention further provides use of a compound of
Formula (I), or a pharmaceutically acceptable salt thereof, for the
preparation of a medicament for use in any of the methods described
herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0020] FIG. 1 shows an X-Ray Powder Diffraction (XRPD) pattern
characteristic of the crystalline compound of Example 253.
[0021] FIG. 2 shows a Differential Scanning Calorimetry (DSC)
thermogram characteristic of the crystalline compound of Example
253.
[0022] FIG. 3 shows a TGA thermogram characteristic of the
crystalline compound of Example 253.
[0023] FIG. 4 shows an X-Ray Powder Diffraction (XRPD) pattern
characteristic of the crystalline hydrochloric acid salt of Example
254.
[0024] FIG. 5 shows a Differential Scanning Calorimetry (DSC)
thermogram characteristic of the crystalline hydrochloric acid salt
of Example 254.
[0025] FIG. 6 shows a TGA thermogram characteristic of the
crystalline hydrochloric acid salt of Example 254.
[0026] FIG. 7 shows an X-Ray Powder Diffraction (XRPD) pattern
characteristic of the crystalline benzenesulfonic acid salt of
Example 255.
[0027] FIG. 8 shows a Differential Scanning Calorimetry (DSC)
thermogram characteristic of the crystalline benzenesulfonic acid
salt of Example 255.
[0028] FIG. 9 shows a TGA thermogram characteristic of the
crystalline benzenesulfonic acid salt of Example 255.
DETAILED DESCRIPTION
[0029] Compounds The present application provides, inter alia, a
compound of Formula (I):
##STR00003##
or a pharmaceutically acceptable salt thereof, wherein:
[0030] X.sup.1 is N or CR.sup.1;
[0031] X.sup.2 is N or CR.sup.2;
[0032] X.sup.3 is N or CR.sup.3;
[0033] X.sup.4 is N or CR.sup.4;
[0034] X.sup.5 is N or CR.sup.5;
[0035] X.sup.6 is N or CR.sup.6;
[0036] X.sup.3, X.sup.4, X.sup.5 and X.sup.6 are not simultaneously
N;
[0037] R.sup.7 is H or C.sub.1-6 alkyl optionally substituted with
1, 2 or 3 groups independently selected from halo, OH, oxo, CN,
C.sub.3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C.sub.6-10
aryl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy,
NH.sub.2, C.sub.1-6 alkyl-NH-- and (C.sub.1-6 alkyl).sub.2N--;
[0038] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and
R.sup.7 are each independently selected from H, D, halo, oxo,
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.6-10
aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl, 4-14
membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-14 membered
heteroaryl)-C.sub.1-4 alkyl-, (4-14 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, CN, NO.sub.2, OR.sup.a1,
SR.sup.a1, NHOR.sup.a1, C(O)R.sup.a1, C(O)NR.sup.a1R.sup.a1,
C(O)OR.sup.a1, OC(O)R.sup.a1, OC(O)NR.sup.a1R.sup.a1, NHR.sup.a1,
NR.sup.a1R.sup.a1, NR.sup.a1C(O)R.sup.a1, NR.sup.a1C(O)OR.sup.a1,
NR.sup.a1C(O)NR.sup.a1R.sup.a1, C(.dbd.NR.sup.a1)R.sup.a1,
C(.dbd.NR.sup.a1)NR.sup.a1R.sup.a1,
NR.sup.a1C(.dbd.NR.sup.a1)NR.sup.a1R.sup.a1,
NR.sup.a1C(.dbd.NOH)NR.sup.a1R.sup.a1
NR.sup.a1C(.dbd.NCN)NR.sup.a1R.sup.a1, NR.sup.a1S(O)R.sup.a1,
NR.sup.a1S(O).sub.2R.sup.a1, NR.sup.a1S(O).sub.2NR.sup.a1R.sup.a1,
S(O)R.sup.a1, S(O)NR.sup.a1R.sup.a1, S(O).sub.2R.sup.a1, SF.sub.5,
--P(O)R.sup.a1R.sup.a1, --P(O)(OR.sup.a1)(OR.sup.a1),
B(OR.sup.a1).sub.2 and S(O).sub.2NR.sup.a1R.sup.a1, wherein the
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered
heteroaryl, 4-14 membered heterocycloalkyl, C.sub.6-10
aryl-C.sub.1-4 alkyl-, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-,
(5-14 membered heteroaryl)-C.sub.1-4 alkyl-, and (4-14 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.1, R.sup.2, R3, R4,
R.sup.5, R.sup.6 and R.sup.7 are each optionally substituted with
1, 2, 3, 4 or 5 independently selected R.sup.b substituents;
[0039] R.sup.9 is H, D, CN, C(O), NH.sub.2, --OH, --COOH,
--NH(C.sub.1-6 alkyl), --NH(C.sub.1-6 alkyl).sub.2, C.sub.1-6
alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy or C.sub.1-6
haloalkoxy, wherein the C.sub.1-6 alkyl is optionally substituted
with 1, 2 or 3 independently selected R.sup.q substituents;
[0040] R.sup.10 is selected from H, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy,
C.sub.1-6 haloalkoxy, C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10
membered heteroaryl, 4-14 membered heterocycloalkyl, C.sub.6-10
aryl-C.sub.1-4 alkyl-, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-,
(5-14 membered heteroaryl)-C.sub.1-4 alkyl-, (4-14 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, OR.sup.a2, SR.sup.a2,
NHOR.sup.a2, C(O)R.sup.a2, C(O)NR.sup.a2R.sup.a2, C(O)OR.sup.a2,
NHR.sup.a2, NR.sup.a2R.sup.a2, NR.sup.a2C(O)R.sup.a2,
NR.sup.a2C(O)OR.sup.a2, NR.sup.a2C(O)NR.sup.a2R.sup.a2,
C(.dbd.NR.sup.a2)R.sup.a2, C(.dbd.NR.sup.a2)NR.sup.a2R.sup.a2,
NR.sup.a2C(.dbd.NR.sup.a2)NR.sup.a2R.sup.a2, NR.sup.a2S(O)R.sup.a2,
NR.sup.a2S(O).sub.2R.sup.a2, NR.sup.a2S(O).sub.2NR.sup.a2R.sup.a2,
S(O)R.sup.a2, S(O)NR.sup.a2R.sup.a2, S(O).sub.2R.sup.a2,
S(O).sub.2NR.sup.a2R.sup.a2, wherein the C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.6-10 aryl,
C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl, 4-14 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-14 membered heteroaryl)-C.sub.14
alkyl-, and (4-14 membered heterocycloalkyl)-C.sub.1-4 alkyl- of
R.sup.10 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7
or 8 independently selected R.sup.b substituents;
[0041] L is
##STR00004##
or --SO.sub.2--, wherein each R.sup.11 is independently H,
C.sub.1-6 alkyl, or C.sub.3-10 cycloalkyl optionally substituted
with 1 or 2 R.sup.q substituents and wherein the single wavy line
indicates the point of attachment to R.sup.10 and the double wavy
line indicates the point of attachment to the 6-membered ring
A;
[0042] or when L is
##STR00005##
R.sup.10 and R.sup.11 optionally taken together with the nitrogen
atom to which they are attached, form a 4 to 14 membered
heterocycloalkyl or a 4 to 14 membered heterocycloalkyl-C.sub.1-4
alkyl- having 0 to 4 additional heteroatoms as a ring member, each
of which is independently selected from N, O and S, wherein the 4
to 14-membered heterocycloalkyl formed by R.sup.10, R.sup.11 and N
is optionally substituted with 1, 2, 3, 4, 5, 6, 7 or 8
independently selected R.sup.b substituents;
[0043] R.sup.a1 and R.sup.a2 are each independently selected from
H, D, C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10
membered heteroaryl, 4-14 membered heterocycloalkyl, C.sub.6-10
aryl-C.sub.1-4 alkyl-, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-,
(5-10 membered heteroaryl)-C.sub.1-4 alkyl-, and (4-14 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, wherein the C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-14 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered heteroaryl)-C.sub.1-4
alkyl- and (4-14 membered heterocycloalkyl)-C.sub.1-4 alkyl- of
R.sup.a and R.sup.a2 are each optionally substituted with 1, 2, 3,
4, or 5 independently selected Rd substituents;
[0044] each R.sup.b substituent is independently selected from D,
halo, oxo, C.sub.1-4 alkyl, C.sub.1-6 alkoxy, C.sub.1-4 haloalkyl,
C.sub.1-4 haloalkoxy, C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10
membered heteroaryl, 4-14 membered heterocycloalkyl, C.sub.6-10
aryl-C.sub.1-4 alkyl-, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-,
(5-10 membered heteroaryl)-C.sub.1-4 alkyl-, (4-14 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, CN, OH, NH.sub.2, NO.sub.2,
NHOR.sup.c, OR.sup.c, SR.sup.c, C(O)R.sup.c, C(O)NR.sup.cR.sup.c,
C(O)OR.sup.c, OC(O)R.sup.c, OC(O)NR.sup.cR.sup.c,
C(.dbd.NR.sup.c)NR.sup.cR.sup.c,
NR.sup.cC(.dbd.NR.sup.c)NR.sup.cR.sup.c,
NR.sup.cC(.dbd.NOH)NR.sup.cR.sup.c,
NR.sup.cC(.dbd.NCN)NR.sup.cR.sup.c, SF.sub.5, --P(O)R.sup.cR.sup.c,
--P(O)(OR.sup.c)(OR.sup.c), NHR.sup.c, NR.sup.cR.sup.c,
NR.sup.cC(O)R.sup.c, NR.sup.cC(O)OR.sup.c,
NR.sup.cC(O)NR.sup.cR.sup.c, NR.sup.cS(O)R.sup.c,
NR.sup.cS(O).sub.2R.sup.c, NR.sup.cS(O).sub.2NR.sup.cR.sup.c,
S(O)R.sup.c, S(O)NR.sup.cR.sup.c, S(O).sub.2R.sup.c or
S(O).sub.2NR.sup.cR.sup.c; wherein the C.sub.1-4 alkyl, C.sub.1-6
alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, C.sub.6-10 aryl,
C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl, 4-14 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered heteroaryl)-C.sub.1-4
alkyl-and (4-14 membered heterocycloalkyl)-C.sub.1-4 alkyl- of
R.sup.b are each further optionally substituted with 1, 2, or 3
independently selected Rd substituents;
[0045] each R.sup.c is independently selected from H, D, C.sub.1-6
alkyl, C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered
heteroaryl)-C.sub.1-4 alkyl-, and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, wherein the C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered heteroaryl)-C.sub.1-4
alkyl- and (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl- of
R.sup.c are each optionally substituted with 1, 2, 3, 4, or 5
independently selected R.sup.f substituents;
[0046] each R.sup.f is independently selected from C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered
heteroaryl)-C.sub.1-4 alkyl-, and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, halo, CN, NHOR.sup.g, OR.sup.g,
SR.sup.g, C(O)R.sup.g, C(O)NR.sup.gR.sup.g, C(O)OR.sup.g,
OC(O)R.sup.g, OC(O)NR.sup.gR.sup.g, NHR.sup.g, NR.sup.gR.sup.g,
NR.sup.gC(O)R.sup.g, NR.sup.gC(O)NR.sup.gR.sup.g,
NR.sup.gC(O)OR.sup.g, C(.dbd.NR.sup.g)NR.sup.gR.sup.g,
NR.sup.gC(.dbd.NR.sup.g)NR.sup.gR.sup.g,
NR.sup.gC(.dbd.NOH)NR.sup.gR.sup.g,
NR.sup.gC(.dbd.NCN)NR.sup.gR.sup.g, SF.sub.5, --P(O)R.sup.gR.sup.g,
--P(O)(OR.sup.g)(OR.sup.g), S(O)R.sup.g, S(O)NR.sup.gR.sup.g,
S(O).sub.2R.sup.g, NR.sup.gS(O).sub.2R.sup.g,
NR.sup.gS(O).sub.2NR.sup.gR.sup.g, and S(O).sub.2NR.sup.gR.sup.g;
wherein the C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, C.sub.3-10 cycloalkyl,
5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,
C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10 cycloalkyl-C.sub.1-4
alkyl-, (5-10 membered heteroaryl)-C.sub.1-4 alkyl-, and (4-10
membered heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.f are each
optionally substituted with 1, 2, 3, 4, or 5 independently selected
R.sup.n substituents;
[0047] each R.sup.n is independently selected from C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, halo, CN, R.sup.o, NHOR.sup.o, OR.sup.o,
SR.sup.o, C(O)R.sup.o, C(O)NR.sup.oR.sup.o, C(O)OR.sup.o,
OC(O)R.sup.o, OC(O)NR.sup.oR.sup.o, NHR.sup.o, NR.sup.oR.sup.o,
NR.sup.oC(O)R.sup.o, NR.sup.oC(O)NR.sup.oR.sup.o,
NR.sup.oC(O)OR.sup.o, C(.dbd.NR.sup.o)NR.sup.oR.sup.o,
NR.sup.oC(.dbd.NR.sup.o)NR.sup.oR.sup.o,
NR.sup.oC(.dbd.NOH)NR.sup.oR.sup.o,
NR.sup.oC(.dbd.NCN)NR.sup.oR.sup.o, SF.sub.5, --P(O)R.sup.oR.sup.o,
--P(O)(OR.sup.o)(OR.sup.o), S(O)R.sup.o, S(O)NR.sup.oR.sup.o,
S(O).sub.2R.sup.o, NR.sup.oS(O).sub.2R.sup.o,
NR.sup.oS(O).sub.2NR.sup.oR.sup.o, and
S(O).sub.2NR.sup.oR.sup.o;
[0048] each R.sup.d is independently selected from D, oxo,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, halo, C.sub.3-10 cycloalkyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.14 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered heteroaryl)-C.sub.1-4
alkyl-, and (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl-, CN,
NH.sub.2, NHOR.sup.e, OR.sup.e, SR.sup.e, C(O)R.sup.e,
C(O)NR.sup.eR.sup.e, C(O)OR.sup.e, OC(O)R.sup.e,
OC(O)NR.sup.eR.sup.e, NHR.sup.e, NR.sup.eR.sup.e,
NR.sup.eC(O)R.sup.e, NR.sup.eC(O)NR.sup.eR.sup.e,
NR.sup.eC(O)OR.sup.e, C(.dbd.NR.sup.e)NR.sup.eR.sup.e,
NR.sup.eC(.dbd.NR.sup.e)NR.sup.eR.sup.e,
NR.sup.eC(.dbd.NOH)NR.sup.eR.sup.e,
NR.sup.eC(.dbd.NCN)NR.sup.eR.sup.e, SF.sub.5, --P(O)R.sup.eR.sup.e,
--P(O)(OR.sup.e)(OR.sup.e), S(O)R.sup.e, S(O)NR.sup.eR.sup.e,
S(O).sub.2R, NR.sup.eS(O).sub.2R.sup.e,
NR.sup.eS(O).sub.2NR.sup.eR.sup.e, and S(O).sub.2NR.sup.eR.sup.e,
wherein the C.sub.1-6 alkyl, C.sub.3-10 cycloalkyl, C.sub.6-10
aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,
C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10 cycloalkyl-C.sub.1-4
alkyl-, (5-10 membered heteroaryl)-C.sub.1-4 alkyl-, and (4-10
membered heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.d are each
optionally substituted with 1, 2, or 3 independently selected
R.sup.f substituents;
[0049] each R.sup.e is independently selected from H, D, CN,
C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered
heteroaryl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl-C.sub.1-4 alkyl-, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-,
(5-10 membered heteroaryl)-C.sub.1-4 alkyl-, and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, wherein the C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered heteroaryl)-C.sub.1-4
alkyl- and (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl- of
R.sup.e are each optionally substituted with 1, 2 or 3
independently selected R.sup.q substituents;
[0050] each R.sup.g is independently selected from H, D, C.sub.1-6
alkyl, C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered
heteroaryl)-C.sub.1-4 alkyl-, and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, wherein the C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl,
C.sub.3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered heteroaryl)-C.sub.1-4
alkyl- and (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl- of
R.sup.g are each optionally substituted with 1, 2 or 3
independently selected R.sup.p substituents;
[0051] each R.sup.p is independently selected from C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered
heteroaryl)-C.sub.1-4 alkyl-, and (4-membered
heterocycloalkyl)-C.sub.1-4 alkyl-, halo, CN, NHOR.sup.r, OR.sup.r,
SR.sup.r, C(O)R.sup.r, C(O)NR.sup.rR.sup.r, C(O)OR.sup.r,
OC(O)R.sup.r, OC(O)NR.sup.rR.sup.r, NHR.sup.r, NR.sup.rR.sup.r,
NR.sup.rC(O)R.sup.r, NR.sup.rC(O)NR.sup.rR.sup.r,
NR.sup.rC(O)OR.sup.r, C(.dbd.NR.sup.r)NR.sup.rR.sup.r,
NR.sup.rC(.dbd.NR.sup.r)NR.sup.rR.sup.r,
NR.sup.rC(.dbd.NOH)NR.sup.rR.sup.r, NR.sup.rC(.dbd.NCN)NR.sup.r,
SF.sub.5, --P(O)R.sup.rR.sup.r, --P(O)(OR.sup.r)(OR.sup.r),
S(O)R.sup.r, S(O)NR.sup.r, S(O).sub.2R.sup.r,
NR.sup.rS(O).sub.2R.sup.r, NR.sup.rS(O).sub.2NR.sup.rR.sup.r, and
S(O).sub.2NR.sup.rR.sup.r;
[0052] or any two R.sup.a1 substituents together with the nitrogen
atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or
10-membered heterocycloalkyl group optionally substituted with 1, 2
or 3 independently selected Rh substituents;
[0053] each R.sup.h is independently selected from C.sub.1-6 alkyl,
C.sub.3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C.sub.6-10
aryl, 5-6 membered heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-4
alkyl-, (5-6 membered heteroaryl)-C.sub.1-4 alkyl-, (4-7 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, C.sub.1-6 haloalkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, halo, CN, OR.sup.i, SR.sup.i,
NHOR.sup.i, C(O)R.sup.i, C(O)NR.sup.iR.sup.i, C(O)OR.sup.i,
OC(O)R.sup.i, OC(O)NR.sup.iR.sup.i, NHR.sup.i, NR.sup.iR.sup.i,
NR.sup.iC(O)R.sup.i, NR.sup.iC(O)NR.sup.iR.sup.i,
NR.sup.iC(O)OR.sup.i, C(.dbd.NR.sup.i)NR.sup.iR.sup.i,
NR.sup.iC(.dbd.NR.sup.i)NR.sup.iR.sup.i,
NR.sup.iC(.dbd.NOH)NR.sup.iR.sup.i,
NR.sup.iC(.dbd.NCN)NR.sup.iR.sup.i, SF.sub.5, --P(O)R.sup.iR.sup.i,
--P(O)(OR.sup.i)(OR.sup.i), S(O)R.sup.i, S(O)NR.sup.iR.sup.i,
S(O).sub.2R.sup.i, NR.sup.iS(O).sub.2R.sup.i,
NR.sup.iS(O).sub.2NR.sup.iR.sup.i, and S(O).sub.2NR.sup.iR.sup.i,
wherein the C.sub.1-6 alkyl, C.sub.3-10 cycloalkyl, 4-7 membered
heterocycloalkyl, C.sub.6-10 aryl, 5-6 membered heteroaryl,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-6 membered
heteroaryl)-C.sub.1-4 alkyl-, (4-7 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.h are each further
optionally substituted by 1, 2, or 3 independently selected R.sup.j
substituents;
[0054] each R.sup.j is independently selected from C.sub.3-6
cycloalkyl, C.sub.6-10 aryl, 5 or 6-membered heteroaryl, C.sub.2-4
alkenyl, C.sub.2-4 alkynyl, halo, C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, CN, NHOR.sup.k, OR.sup.k, SR.sup.k, C(O)R.sup.k,
C(O)NR.sup.kR.sup.k, C(O)OR.sup.k, OC(O)R.sup.k,
OC(O)NR.sup.kR.sup.k, NHR.sup.k, NR.sup.kR.sup.k,
NR.sup.kC(O)R.sup.k, NR.sup.kC(O)NR.sup.kR.sup.k,
NR.sup.kC(O)OR.sup.k, C(.dbd.NR.sup.k)NR.sup.kR.sup.k,
NR.sup.kC(.dbd.NR.sup.k)NR.sup.kR.sup.k,
NR.sup.kC(.dbd.NOH)NR.sup.kR.sup.k,
NR.sup.kC(.dbd.NCN)NR.sup.kR.sup.k, SF.sub.5, --P(O)R.sup.kR.sup.k,
--P(O)(OR.sup.k)(OR.sup.k), S(O)R.sup.k, S(O)NR.sup.kR.sup.k,
S(O).sub.2R.sup.k, NR.sup.kS(O).sub.2R.sup.k,
NR.sup.kS(O).sub.2NR.sup.kR.sup.k, and S(O).sub.2NR.sup.kR.sup.k;
or two R.sup.j groups attached to the same carbon atom of the 4- to
10-membered heterocycloalkyl taken together with the carbon atom to
which they attach form a C.sub.3-6 cycloalkyl or 4- to 6-membered
heterocycloalkyl having 1-2 heteroatoms as ring members selected
from O, N or S;
[0055] or any two R.sup.a2 substituents together with the nitrogen
atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or
10-membered heterocycloalkyl group optionally substituted with 1, 2
or 3 R.sup.h substituents;
[0056] or any two R.sup.c substituents together with the nitrogen
atom to which they are attached form a 4-, 5-, 6-, or 7-membered
heterocycloalkyl group optionally substituted with 1, 2, or 3
independently selected R.sup.h substituents;
[0057] or any two R.sup.e substituents together with the nitrogen
atom to which they are attached form a 4-, 5-, 6-, or 7-membered
heterocycloalkyl group optionally substituted with 1, 2, or 3
independently selected R.sup.h substituents;
[0058] or any two R.sup.g substituents together with the nitrogen
atom to which they are attached form a 4-, 5-, 6-, or 7-membered
heterocycloalkyl group optionally substituted with 1, 2, or 3
independently selected R.sup.h substituents;
[0059] or any two R.sup.i substituents together with the nitrogen
atom to which they are attached form a 4-, 5-, 6-, or 7-membered
heterocycloalkyl group optionally substituted with 1, 2, or 3
independently selected R.sup.h substituents;
[0060] or any two R.sup.k substituents together with the nitrogen
atom to which they are attached form a 4-, 5-, 6-, or 7-membered
heterocycloalkyl group optionally substituted with 1, 2, or 3
independently selected R.sup.h substituents;
[0061] or any two R.sup.o substituents together with the nitrogen
atom to which they are attached form a 4-, 5-, 6-, or 7-membered
heterocycloalkyl group optionally substituted with 1, 2, or 3
independently selected R.sup.h substituents;
[0062] or any two R.sup.r substituents together with the nitrogen
atom to which they are attached form a 4-, 5-, 6-, or 7-membered
heterocycloalkyl group optionally substituted with 1, 2, or 3
independently selected R.sup.h substituents;
[0063] each R.sup.i, R.sup.k, R.sup.o or R.sup.r is independently
selected from H, D, C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl,
C.sub.6-10 aryl, 5 or 6-membered heteroaryl, C.sub.1-4 haloalkyl,
C.sub.2-4 alkenyl, and C.sub.2-4 alkynyl, wherein the C.sub.1-4
alkyl, C.sub.3-6 cycloalkyl, C.sub.6-10 aryl, 5 or 6-membered
heteroaryl, C.sub.2-4 alkenyl, and C.sub.2-4 alkynyl of R, R.sup.k,
R.sup.o or R.sup.r are each optionally substituted with 1, 2 or 3
independently selected R.sup.q substituents;
[0064] each R.sup.q is independently selected from D, OH, CN,
--COOH, NH.sub.2, halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, C.sub.1-4 alkylthio,
phenyl, 5-6 membered heteroaryl, C.sub.3_6 cycloalkyl, 4-6 membered
heterocycloalkyl, --CONHR.sup.12, --NHC(O)R.sup.2, --OC(O)R.sup.12,
--C(O)OR.sup.2, --C(O)R.sup.12, --SO.sub.2R.sup.12,
--NHSO.sub.2R.sup.12, --SO.sub.2NHR.sup.12 and NR.sup.12R.sup.12,
wherein the C.sub.1-6 alkyl, phenyl, 4-6 membered heterocycloalkyl
and 5-6 membered heteroaryl of R.sup.g are each optionally
substituted with OH, CN, --COOH, NH.sub.2, C.sub.1-6 alkoxy,
C.sub.3-6 cycloalkyl or 4-6 membered heterocycloalkyl;
[0065] and each R.sup.12 is independently C.sub.1-6 alkyl;
[0066] provided that:
[0067] when R.sup.7 is C.sub.1-6 alkyl, R.sup.10-L- is other than
cyclopropylsulfamoyl and methanesulfonamido;
[0068] when R.sup.7 is cyclopropylmethyl, R.sup.10-L- is other than
methanesulfonamido;
[0069] when R.sup.7 is 2-(4-morpholino)ethyl, R.sup.10-L- is other
than methanesulfonyl; and
[0070] the compound is other than
3-(8-aminoimidazo[1,2-a]pyridin-3-yl)-2-(1H-tetrazol-5-yl)benzenesulfonam-
ide.
[0071] In some embodiments:
[0072] X.sup.1 is N or CR.sup.1;
[0073] X.sup.2 is N or CR.sup.2;
[0074] X.sup.3 is N or CR.sup.3;
[0075] X.sup.4 is N or CR.sup.4;
[0076] X.sup.5 is N or CR.sup.5;
[0077] X.sup.6 is N or CR.sup.6;
[0078] X.sup.3, X.sup.4, X.sup.5 and X.sup.6 are not simultaneously
N;
[0079] R.sup.7 is H or C.sub.1-6 alkyl optionally substituted with
1, 2 or 3 groups independently selected from halo, OH, oxo, CN,
C.sub.3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C.sub.1-6
haloalkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, NH.sub.2,
C.sub.1-6 alkyl-NH-- and (C.sub.1-6 alkyl).sub.2N--; R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are each
independently selected from H, halo, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, C.sub.1-6
haloalkoxy, C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered
heteroaryl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl-C.sub.1-4 alkyl-, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-,
(5-14 membered heteroaryl)-C.sub.1-4 alkyl-, (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, CN, NO.sub.2, OR.sup.a1,
SR.sup.a1, NHOR.sup.a1, C(O)R.sup.a1, C(O)NR.sup.a1R.sup.a1,
C(O)OR.sup.a1, OC(O)R.sup.a1, OC(O)NR.sup.a1R.sup.a1, NHR.sup.a1,
NR.sup.a1R.sup.a1, NR.sup.a1C(O)R.sup.a1, NR.sup.a1C(O)OR.sup.a1,
NR.sup.a1C(O)NR.sup.a1R.sup.a1, C(.dbd.NR.sup.a1)R.sup.a1mi,
C(.dbd.NR.sup.a1)NR.sup.a1R.sup.a1
NR.sup.a1C(.dbd.NR.sup.a1)NR.sup.a1R.sup.a1,
NR.sup.a1C(.dbd.NOH)NR.sup.a1R.sup.a1,
NR.sup.a1C(.dbd.NCN)NR.sup.a1R.sup.a1, NR.sup.a1S(O)R.sup.a1,
NR.sup.a1S(O).sub.2R.sup.a1, NR.sup.a1S(O).sub.2NR.sup.a1R.sup.a1,
S(O)R.sup.a1, S(O)NR.sup.a1R.sup.a1, S(O).sub.2R.sup.a1, SF.sub.5,
--P(O)R.sup.a1R.sup.a1, --P(O)(OR.sup.a1)(OR.sup.a1) and
S(O).sub.2NR.sup.a1R.sup.a1, wherein the C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, C.sub.3-10 cycloalkyl,
5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,
C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10 cycloalkyl-C.sub.1-4
alkyl-, (5-14 membered heteroaryl)-C.sub.1-4 alkyl-, and (4-10
membered heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are each optionally
substituted with 1, 2, 3, 4 or 5 independently selected R.sup.b
substituents;
[0080] R.sup.9 is H, CN, NH.sub.2, --OH, --COOH, --NH(C.sub.1-6
alkyl), --NH(C.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.1-6 alkoxy or C.sub.1-6 haloalkoxy, wherein the
C.sub.1-6 alkyl is optionally substituted with 1, 2 or 3
independently selected R.sup.q substituents;
[0081] R.sup.10 is selected from H, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, C.sub.1-6
haloalkoxy, C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered
heteroaryl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl-C.sub.1-4 alkyl-, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-,
(5-14 membered heteroaryl)-C.sub.1-4 alkyl-, (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, OR.sup.a2, SR.sup.a2,
NHOR.sup.a2, C(O)R.sup.a2, C(O)NR.sup.a2R.sup.a2, C(O)OR.sup.a2,
NHR.sup.a2, NR.sup.a2R.sup.a2, NR.sup.a2C(O)R.sup.a2,
NR.sup.a2C(O)OR.sup.a2, NR.sup.a2C(O)NR.sup.a2R.sup.a2,
C(.dbd.NR.sup.a2)R.sup.a2, C(.dbd.NR.sup.a2)NR.sup.a2R.sup.a2,
NR.sup.a2C(.dbd.NR.sup.a2)NR.sup.a2R.sup.a2, NR.sup.a2S(O)R.sup.a2,
NR.sup.a2S(O).sub.2R.sup.a2, NR.sup.a2S(O).sub.2NR.sup.a2R.sup.a2,
S(O)R.sup.a2, S(O)NR.sup.a2R.sup.a2, S(O).sub.2R.sup.a2, and
S(O).sub.2NR.sup.a2R.sup.a2, wherein the C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, C.sub.3-10 cycloalkyl,
5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,
C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10 cycloalkyl-C.sub.1-4
alkyl-, (5-14 membered heteroaryl)-C.sub.1-4 alkyl-, and (4-10
membered heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.10 are each
optionally substituted with 1, 2, 3, 4 or 5 independently selected
R.sup.b substituents;
[0082] L is
##STR00006##
or --SO.sub.2--, wherein each R.sup.11 is independently H or
C.sub.1-6 alkyl optionally substituted with 1 or 2 R.sup.q
substituents and wherein the single wavy line indicates the point
of attachment to R.sup.10 and the double wavy line indicates the
point of attachment to the 6-membered ring A;
[0083] or when L is
##STR00007##
R.sup.10 and R.sup.11 optionally taken together with the nitrogen
atom to which they are attached, form 4-, 5-, 6- or 7-membered
heterocycloalkyl having 0 to 1 additional heteroatom as a ring
member selected from N, O and S, wherein the 4-, 5-, 6- or
7-membered heterocycloalkyl formed by R.sup.10, R.sup.11 and N is
optionally substituted with 1, 2 or 3 independently selected
R.sup.q substituents;
[0084] or two substituents attached to the same ring carbon atom of
the heterocycloalkyl formed by R.sup.10 and R.sup.11, taken
together with the carbon atom to which they are attached form
C.sub.3-6 cycloalkyl, optionally substituted with 1, 2 or 3
independently selected R.sup.q substituents; R.sup.a1 and R.sup.a2
are each independently selected from H, C.sub.1-6 alkyl, C.sub.1-4
haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl,
C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered heteroaryl)-C.sub.1-4
alkyl-, and (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl-,
wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered
heteroaryl)-C.sub.1-4 alkyl- and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.a and R.sup.a2 are each
optionally substituted with 1, 2, 3, 4, or 5 independently selected
R.sup.d substituents;
[0085] each R.sup.b substituent is independently selected from
halo, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered
heteroaryl)-C.sub.1-4 alkyl-, (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, CN, OH, NH.sub.2, NO.sub.2,
NHOR.sup.c, OR.sup.c, SR, C(O)R.sup.c, C(O)NR.sup.cR.sup.c,
C(O)OR.sup.c, OC(O)R.sup.c, OC(O)NR.sup.cR.sup.c,
C(.dbd.NR.sup.c)NR.sup.cR.sup.c,
NR.sup.cC(.dbd.NR.sup.c)NR.sup.cR.sup.c,
NR.sup.cC(.dbd.NOH)NR.sup.cR.sup.c,
NR.sup.cC(.dbd.NCN)NR.sup.cR.sup.c, SF.sub.5, --P(O)R.sup.cR.sup.c,
--P(O)(OR.sup.c)(OR.sup.c), NHR.sup.c, NR.sup.cR.sup.c,
NR.sup.cC(O)R.sup.c, NR.sup.cC(O)OR.sup.c,
NR.sup.cC(O)NR.sup.cR.sup.c, NR.sup.cS(O)R.sup.c,
NR.sup.cS(O).sub.2R.sup.c, NR.sup.cS(O).sub.2NR.sup.cR.sup.c,
S(O)R.sup.c, S(O)NR.sup.cR.sup.c, S(O).sub.2R.sup.c or
S(O).sub.2NR.sup.cR.sup.c; wherein the C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, C.sub.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.14 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered heteroaryl)-C.sub.1-4
alkyl-and (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl- of
R.sup.c are each further optionally substituted with 1, 2, or 3
independently selected R.sup.d substituents;
[0086] each R.sup.c is independently selected from H, C.sub.1-6
alkyl, C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered
heteroaryl)-C.sub.1-4 alkyl-, and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, wherein the C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered heteroaryl)-C.sub.1-4
alkyl- and (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl- of
R.sup.c are each optionally substituted with 1, 2, 3, 4, or 5
independently selected R.sup.f substituents;
[0087] each R.sup.f is independently selected from C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered
heteroaryl)-C.sub.1-4 alkyl-, and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, halo, CN, NHOR.sup.g, OR.sup.g,
SR.sup.g, C(O)R.sup.g, C(O)NR.sup.gR.sup.g, C(O)OR.sup.g,
OC(O)R.sup.g, OC(O)NR.sup.gR.sup.g, NHR.sup.g, NR.sup.gR.sup.g,
NR.sup.gC(O)R.sup.g, NR.sup.gC(O)NR.sup.gR.sup.g,
NR.sup.gC(O)OR.sup.g, C(.dbd.NR.sup.g)NR.sup.gR.sup.g,
NR.sup.gC(.dbd.NR.sup.g)NR.sup.gR.sup.g,
NR.sup.gC(.dbd.NOH)NR.sup.gR.sup.g,
NR.sup.gC(.dbd.NCN)NR.sup.gR.sup.g, SF.sub.5, --P(O)R.sup.gR.sup.g,
--P(O)(OR.sup.g)(OR.sup.g), S(O)R.sup.g, S(O)NR.sup.gR.sup.g,
S(O).sub.2R.sup.g, NR.sup.gS(O).sub.2R.sup.g,
NR.sup.gS(O).sub.2NR.sup.gR.sup.g, and S(O).sub.2NR.sup.gR.sup.g;
wherein the C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, C.sub.3-10 cycloalkyl,
5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,
C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10 cycloalkyl-C.sub.1-4
alkyl-, (5-10 membered heteroaryl)-C.sub.1-4 alkyl-, and (4-10
membered heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.f are each
optionally substituted with 1, 2, 3, 4, or 5 independently selected
R.sup.n substituents;
[0088] each R.sup.n is independently selected from C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, halo, CN, R.sup.o, NHOR.sup.o, OR.sup.o,
SR.sup.o, C(O)R.sup.o, C(O)NR.sup.oR.sup.o, C(O)OR.sup.o,
OC(O)R.sup.o, OC(O)NR.sup.oR.sup.o, NHR.sup.o, NR.sup.oR.sup.o,
NR.sup.oC(O)R.sup.o, NR.sup.oC(O)NR.sup.oR.sup.o,
NR.sup.oC(O)OR.sup.o, C(.dbd.NR.sup.o)NR.sup.oR.sup.o,
NR.sup.oC(.dbd.NR.sup.o)NR.sup.oR.sup.o,
NR.sup.oC(.dbd.NOH)NR.sup.oR.sup.o,
NR.sup.oC(.dbd.NCN)NR.sup.oR.sup.o, SF.sub.5, --P(O)R.sup.oR.sup.o,
--P(O)(OR.sup.o)(OR.sup.o), S(O)R.sup.o, S(O)NR.sup.oR.sup.o,
S(O).sub.2R.sup.o, NR.sup.oS(O).sub.2R.sup.o,
NR.sup.oS(O).sub.2NR.sup.oR.sup.o, and
S(O).sub.2NR.sup.oR.sup.o;
[0089] each R.sup.d is independently selected from C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, halo, C.sub.3-10 cycloalkyl, C.sub.6-10 aryl,
5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,
C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10 cycloalkyl-C.sub.1-4
alkyl-, (5-10 membered heteroaryl)-C.sub.1-4 alkyl-, and (4-10
membered heterocycloalkyl)-C.sub.1-4 alkyl-, CN, NH.sub.2,
NHOR.sup.e, OR.sup.e, SR.sup.e, C(O)R.sup.e, C(O)NR.sup.eR.sup.e,
C(O)OR.sup.e, OC(O)R.sup.e, OC(O)NR.sup.eR.sup.e, NHR.sup.e,
NR.sup.eR.sup.e, NR.sup.eC(O)R.sup.e, NR.sup.eC(O)NR.sup.eR.sup.e,
NR.sup.eC(O)OR.sup.e, C(.dbd.NR.sup.e)NR.sup.eR.sup.e,
NR.sup.eC(.dbd.NR.sup.e)NR.sup.eR.sup.e,
NR.sup.eC(.dbd.NOH)NR.sup.eR.sup.e,
NR.sup.eC(.dbd.NCN)NR.sup.eR.sup.e, SF.sub.5, --P(O)R.sup.eR.sup.e,
--P(O)(OR.sup.e)(OR.sup.e), S(O)R.sup.e, S(O)NR.sup.eR.sup.e,
S(O).sub.2R, NR.sup.eS(O).sub.2R.sup.e,
NR.sup.eS(O).sub.2NR.sup.eR.sup.e, and S(O).sub.2NR.sup.eR.sup.e,
wherein the C.sub.1-6 alkyl, C.sub.3-10 cycloalkyl, C.sub.6-10
aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,
C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10 cycloalkyl-C.sub.1-4
alkyl-, (5-10 membered heteroaryl)-C.sub.1-4 alkyl-, and (4-10
membered heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.d are each
optionally substituted with 1, 2, or 3 independently selected
R.sup.f substituents;
[0090] each R.sup.e is independently selected from H, CN, C.sub.1-6
alkyl, C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered
heteroaryl)-C.sub.1-4 alkyl-, and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, wherein the C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered heteroaryl)-C.sub.1-4
alkyl- and (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl- of
R.sup.e are each optionally substituted with 1, 2 or 3
independently selected R.sup.g substituents;
[0091] each R.sup.g is independently selected from H, C.sub.1-6
alkyl, C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered
heteroaryl)-C.sub.1-4 alkyl-, and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, wherein the C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.14 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered heteroaryl)-C.sub.1-4
alkyl- and (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl- of
R.sup.g are each optionally substituted with 1, 2 or 3
independently selected R.sup.p substituents;
[0092] each R.sup.p is independently selected from C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered
heteroaryl)-C.sub.1-4 alkyl-, and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, halo, CN, NHOR.sup.r, OR.sup.r,
SR.sup.r, C(O)R.sup.r, C(O)NR.sup.rR.sup.r, C(O)OR.sup.r,
OC(O)R.sup.r, OC(O)NR.sup.rR.sup.r, NHR.sup.r, NR.sup.rR.sup.r,
NR.sup.rC(O)R.sup.r, NR.sup.rC(O)NR.sup.r, NR.sup.rC(O)OR.sup.r,
C(.dbd.NR.sup.r)NR.sup.rR.sup.r,
NR.sup.rC(.dbd.NR.sup.r)NR.sup.rR.sup.r,
NR.sup.rC(.dbd.NOH)NR.sup.rR.sup.r,
NR.sup.rC(.dbd.NCN)NR.sup.rR.sup.r, SF.sub.5, --P(O)R.sup.rR.sup.r,
--P(O)(OR.sup.r)(OR.sup.r), S(O)R.sup.r, S(O)NR.sup.rR.sup.r,
S(O).sub.2R.sup.r, NR.sup.rS(O).sub.2R.sup.r,
NR.sup.rS(O).sub.2NR.sup.rR.sup.r, and
S(O).sub.2NR.sup.rR.sup.r;
[0093] or any two R.sup.a1 substituents together with the nitrogen
atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or
10-membered heterocycloalkyl group optionally substituted with 1, 2
or 3 independently selected R.sup.h substituents;
[0094] each R.sup.h is independently selected from C.sub.1-6 alkyl,
C.sub.3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C.sub.6-10
aryl, 5-6 membered heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-4
alkyl-, (5-6 membered heteroaryl)-C.sub.1-4 alkyl-, (4-7 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, C.sub.1-6 haloalkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, halo, CN, OR.sup.i, SR.sup.i,
NHOR.sup.i, C(O)R.sup.i, C(O)NR.sup.iR.sup.i, C(O)OR.sup.i,
OC(O)R.sup.i, OC(O)NR.sup.iR.sup.i, NHR.sup.i, NR.sup.iR.sup.i,
NR.sup.iC(O)R.sup.i, NR.sup.iC(O)NR.sup.iR.sup.i,
NR.sup.iC(O)OR.sup.i, C(.dbd.NR.sup.i)NR.sup.iR.sup.i,
NR.sup.iC(.dbd.NR.sup.i)NR.sup.iR.sup.i,
NR.sup.iC(.dbd.NOH)NR.sup.iR.sup.i,
NR.sup.iC(.dbd.NCN)NR.sup.iR.sup.i, SF.sub.5, --P(O)R.sup.iR.sup.i,
--P(O)(OR.sup.i)(OR.sup.i), S(O)R.sup.i, S(O)NR.sup.iR.sup.i,
S(O).sub.2R.sup.i, NR.sup.iS(O).sub.2R.sup.i,
NR.sup.iS(O).sub.2NR.sup.iR.sup.i, and S(O).sub.2NR.sup.iR.sup.i,
wherein the C.sub.1-6 alkyl, C.sub.3-10 cycloalkyl, 4-7 membered
heterocycloalkyl, C.sub.6-10 aryl, 5-6 membered heteroaryl,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-6 membered
heteroaryl)-C.sub.1-4 alkyl-, (4-7 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.h are each further
optionally substituted by 1, 2, or 3 independently selected R.sup.j
substituents;
[0095] each R.sup.j is independently selected from C.sub.3-6
cycloalkyl, C.sub.6-10 aryl, 5 or 6-membered heteroaryl, C.sub.2-4
alkenyl, C.sub.2-4 alkynyl, halo, C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, CN, NHOR.sup.k, OR.sup.k, SR.sup.k, C(O)R.sup.k,
C(O)NR.sup.kR.sup.k, C(O)OR.sup.k, OC(O)R.sup.k,
OC(O)NR.sup.kR.sup.k, NHR.sup.k, NR.sup.kR.sup.k,
NR.sup.kC(O)R.sup.k, NR.sup.kC(O)NR.sup.kR.sup.k,
NR.sup.kC(O)OR.sup.k, C(.dbd.NR.sup.k)NR.sup.kR.sup.k,
NR.sup.kC(.dbd.NR.sup.k)NR.sup.kR.sup.k,
NR.sup.kC(.dbd.NOH)NR.sup.kR.sup.k,
NR.sup.kC(.dbd.NCN)NR.sup.kR.sup.k, SF.sub.5, --P(O)R.sup.kR.sup.k,
--P(O)(OR.sup.k)(OR.sup.k), S(O)R.sup.k, S(O)NR.sup.kR.sup.k,
S(O).sub.2R.sup.k, NR.sup.kS(O).sub.2R.sup.k,
NR.sup.kS(O).sub.2NR.sup.kR.sup.k, and S(O).sub.2NR.sup.kR.sup.k;
or two R.sup.h groups attached to the same carbon atom of the 4- to
10-membered heterocycloalkyl taken together with the carbon atom to
which they attach form a C.sub.3-6 cycloalkyl or 4- to 6-membered
heterocycloalkyl having 1-2 heteroatoms as ring members selected
from O, N or S;
[0096] or any two R.sup.a2 substituents together with the nitrogen
atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or
10-membered heterocycloalkyl group optionally substituted with 1, 2
or 3 R.sup.h substituents;
[0097] or any two R.sup.c substituents together with the nitrogen
atom to which they are attached form a 4-, 5-, 6-, or 7-membered
heterocycloalkyl group optionally substituted with 1, 2, or 3
independently selected R.sup.h substituents;
[0098] or any two R.sup.e substituents together with the nitrogen
atom to which they are attached form a 4-, 5-, 6-, or 7-membered
heterocycloalkyl group optionally substituted with 1, 2, or 3
independently selected R.sup.h substituents;
[0099] or any two R.sup.g substituents together with the nitrogen
atom to which they are attached form a 4-, 5-, 6-, or 7-membered
heterocycloalkyl group optionally substituted with 1, 2, or 3
independently selected R.sup.h substituents;
[0100] or any two R.sup.i substituents together with the nitrogen
atom to which they are attached form a 4-, 5-, 6-, or 7-membered
heterocycloalkyl group optionally substituted with 1, 2, or 3
independently selected R.sup.h substituents;
[0101] or any two R.sup.k substituents together with the nitrogen
atom to which they are attached form a 4-, 5-, 6-, or 7-membered
heterocycloalkyl group optionally substituted with 1, 2, or 3
independently selected R.sup.h substituents;
[0102] or any two R.sup.o substituents together with the nitrogen
atom to which they are attached form a 4-, 5-, 6-, or 7-membered
heterocycloalkyl group optionally substituted with 1, 2, or 3
independently selected R.sup.h substituents;
[0103] or any two R.sup.r substituents together with the nitrogen
atom to which they are attached form a 4-, 5-, 6-, or 7-membered
heterocycloalkyl group optionally substituted with 1, 2, or 3
independently selected R.sup.h substituents;
[0104] each R.sup.i, R.sup.k, R.sup.o or R.sup.r is independently
selected from H, C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, C.sub.6-10
aryl, 5 or 6-membered heteroaryl, C.sub.1-4 haloalkyl, C.sub.2-4
alkenyl, and C.sub.2-4 alkynyl, wherein the C.sub.1-4 alkyl,
C.sub.3-6 cycloalkyl, C.sub.6-10 aryl, 5 or 6-membered heteroaryl,
C.sub.2-4 alkenyl, and C.sub.2-4 alkynyl of R.sup.i, R.sup.k,
R.sup.o or R.sup.r are each optionally substituted with 1, 2 or 3
independently selected R.sup.q substituents;
[0105] each R.sup.q is independently selected from OH, CN, --COOH,
NH.sub.2, halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6
alkoxy, C.sub.1-6 haloalkoxy, C.sub.1-4 alkylthio, phenyl, 5-6
membered heteroaryl, C.sub.3-6 cycloalkyl, 4-6 membered
heterocycloalkyl, --CONHR.sup.12, --NHC(O)R.sup.12,
--OC(O)R.sup.12, --C(O)OR.sup.12, --C(O)R.sup.12,
--SO.sub.2R.sup.12, --NHSO.sub.2R.sup.12, --SO.sub.2NHR.sup.12 and
NR.sup.12R.sup.12, wherein the C.sub.1-6 alkyl, phenyl, 4-6
membered heterocycloalkyl and 5-6 membered heteroaryl of R.sup.q
are each optionally substituted with OH, CN, --COOH, NH.sub.2,
C.sub.1-6 alkoxy, C.sub.3-6 cycloalkyl or 4-6 membered
heterocycloalkyl; and
[0106] each R.sup.12 is independently C.sub.1-6 alkyl;
[0107] provided that:
[0108] when R.sup.7 is C.sub.1-6 alkyl, R.sup.10-L- is other than
cyclopropylsulfamoyl and methanesulfonamido;
[0109] when R.sup.7 is cyclopropylmethyl, R.sup.10-L- is other than
methanesulfonamido;
[0110] when R.sup.7 is 2-(4-morpholino)ethyl, R.sup.10-L- is other
than methanesulfonyl; and the compound is other than
3-(8-aminoimidazo[1,2-a]pyridin-3-yl)-2-(1H-tetrazol-5-yl)benzenesulfonam-
ide.
[0111] In some embodiments of the previous embodiment, each R.sup.b
is independently selected from R.sup.q.
[0112] In some embodiments:
[0113] X.sup.1 is N or CR.sup.1;
[0114] X.sup.2 is N or CR.sup.2;
[0115] X.sup.3 is N or CR.sup.3;
[0116] X.sup.4 is N or CR.sup.4;
[0117] X.sup.5 is N or CR.sup.5;
[0118] X.sup.6 is N or CR.sup.6;
[0119] X.sup.3, X.sup.4, X.sup.5 and X.sup.6 are not simultaneously
N;
[0120] R.sup.7 is H, methyl, or ethyl, wherein said methyl and
ethyl are each optionally substituted with 1, 2 or 3 groups
independently selected from halo, OH, oxo, CN, C.sub.1-6 haloalkyl,
C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, NH.sub.2, C.sub.1-6
alkyl-NH--, and (C.sub.1-6 alkyl).sub.2N--;
[0121] R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are
each independently selected from H, halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.1-6 haloalkoxy, C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10
membered heteroaryl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl-C.sub.1-4 alkyl-, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-,
(5-14 membered heteroaryl)-C.sub.1-4 alkyl-, (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, CN, NO.sub.2, OR.sup.a1,
C(O)R.sup.a1, C(O)NR.sup.a1R.sup.a1, C(O)OR.sup.a1, OC(O)R.sup.a1,
OC(O)NR.sup.a1R.sup.a1, NR.sup.a1R.sup.a1, NR.sup.a1C(O)R.sup.a1
NR.sup.a1C(O)OR.sup.a1, NR.sup.a1C(O)NR.sup.a1R.sup.a1,
NR.sup.a1S(O)R.sup.a1, NR.sup.a1S(O).sub.2R.sup.a1,
NR.sup.a1S(O).sub.2NR.sup.a1R.sup.a1, S(O)R.sup.a1
S(O)NR.sup.a1R.sup.a1, S(O).sub.2R.sup.a1, and
S(O).sub.2NR.sup.a1R.sup.a1, wherein the C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, C.sub.3-10 cycloalkyl,
5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,
C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10 cycloalkyl-C.sub.1-4
alkyl-, (5-14 membered heteroaryl)-C.sub.1-4 alkyl-, and (4-10
membered heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are each optionally
substituted with 1, 2, 3, 4 or 5 independently selected R.sup.b
substituents;
[0122] R.sup.3 is H, halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
C.sub.1-6alkoxy, C.sub.1-6haloalkoxy, OH, CN, NH.sub.2, C.sub.1-6
alkyl-NH--, or (C.sub.1-6 alkyl).sub.2N--;
[0123] R.sup.9 is H, CN, NH.sub.2, --OH, --COOH, --NH(C.sub.1-6
alkyl), --NH(C.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.1-6 alkoxy or C.sub.1-6 haloalkoxy, wherein the
C.sub.1-6 alkyl is optionally substituted with 1, 2 or 3
independently selected R.sup.q substituents;
[0124] R.sup.10 is selected from C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, C.sub.1-6
haloalkoxy, C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered
heteroaryl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl-C.sub.1-4 alkyl-, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-,
(5-14 membered heteroaryl)-C.sub.1-4 alkyl-, (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, OR.sup.a2, C(O)R.sup.a2,
C(O)NR.sup.a2R.sup.a2, C(O)OR.sup.a2, NR.sup.a2R.sup.a2,
NR.sup.a2C(O)R.sup.a2, NR.sup.a2C(O)OR.sup.a2,
NR.sup.a2C(O)NR.sup.a2R.sup.a2, NR.sup.a2S(O)R.sup.a2,
NR.sup.a2S(O).sub.2R.sup.a2, NR.sup.a2S(O).sub.2NR.sup.a2R.sup.a2,
S(O)R.sup.a2, S(O).sub.2R.sup.a2, wherein the C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.14 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-14 membered heteroaryl)-C.sub.1-4
alkyl-, and (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl- of
R.sup.10 are each optionally substituted with 1, 2, 3, 4 or 5
independently selected R.sup.b substituents;
[0125] L is
##STR00008##
or --SO.sub.2--, wherein each R.sup.11 is independently H or
C.sub.1-6 alkyl optionally substituted with 1 or 2 R.sup.q
substituents and wherein the single wavy line indicates the point
of attachment to R.sup.10 and the double wavy line indicates the
point of attachment to the 6-membered ring A;
[0126] or when L is
##STR00009##
R.sup.10 and R.sup.11 optionally taken together with the nitrogen
atom to which they are attached, form 4-, 5-, 6-, 7-, 8-, 9-, or
10-membered heterocycloalkyl having 0 to 1 additional heteroatom as
a ring member selected from N, O and S, wherein the form 4-, 5-,
6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl formed by R.sup.10,
R.sup.11 and N is optionally substituted with 1, 2 or 3
independently selected R.sup.q substituents;
[0127] R.sup.a1 and R.sup.a2 are each independently selected from
H, C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10
membered heteroaryl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl-C.sub.1-4 alkyl-, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-,
(5-10 membered heteroaryl)-C.sub.14 alkyl-, and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, wherein the C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered heteroaryl)-C.sub.1-4
alkyl- and (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl- of
R.sup.a and R.sup.a2 are each optionally substituted with 1, 2, 3,
4, or 5 independently selected R.sup.d substituents;
[0128] each R.sup.b substituent is independently selected from
halo, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered
heteroaryl)-C.sub.1-4 alkyl-, (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, CN, NO.sub.2, OR.sup.c,
C(O)R.sup.c, C(O)NR.sup.cR.sup.c, C(O)OR.sup.c, OC(O)R.sup.c,
OC(O)NR.sup.cR.sup.c, NR.sup.cR.sup.c, NR.sup.cC(O)R.sup.c,
NR.sup.cC(O)OR.sup.c, NR.sup.cC(O)NR.sup.cR.sup.c,
NR.sup.cS(O)R.sup.c, NR.sup.cS(O).sub.2R.sup.c,
NR.sup.cS(O).sub.2NR.sup.cR.sup.c, S(O)R.sup.c,
S(O)NR.sup.cR.sup.c, S(O).sub.2R.sup.c or
S(O).sub.2NR.sup.cR.sup.c; wherein the C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, C.sub.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-membered heteroaryl)-C.sub.1-4
alkyl-and (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl- of
R.sup.b are each further optionally substituted with 1, 2, or 3
independently selected R.sup.d substituents;
[0129] each R.sup.c is independently selected from H, C.sub.1-6
alkyl, C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered
heteroaryl)-C.sub.1-4 alkyl-, and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-;
[0130] each R.sup.d is independently selected from C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, halo, C.sub.3-10 cycloalkyl, C.sub.6-10 aryl,
5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,
C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10 cycloalkyl-C.sub.1-4
alkyl-, (5-10 membered heteroaryl)-C.sub.1-4 alkyl-, and (4-10
membered heterocycloalkyl)-C.sub.1-4 alkyl-, CN, OR.sup.e,
C(O)R.sup.e, C(O)NR.sup.eR.sup.e, C(O)OR.sup.e, OC(O)R.sup.e,
OC(O)NR.sup.eR.sup.e, NR.sup.eR.sup.e, NR.sup.eC(O)R.sup.e,
NR.sup.eC(O)NR.sup.eR.sup.e, NR.sup.eC(O)OR.sup.e, S(O)R.sup.e,
S(O)NR.sup.eR.sup.e, S(O).sub.2R.sup.e, NR.sup.eS(O).sub.2R.sup.e,
NR.sup.eS(O).sub.2NR.sup.eR.sup.e, and
S(O).sub.2NR.sup.eR.sup.e;
[0131] each R.sup.e is independently selected from H, CN, C.sub.1-6
alkyl, C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered
heteroaryl)-C.sub.1-4 alkyl-, and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-;
[0132] or any two R.sup.a1 substituents together with the nitrogen
atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or
10-membered heterocycloalkyl group optionally substituted with 1, 2
or 3 independently selected R.sup.h substituents;
[0133] or any two R.sup.a2 substituents together with the nitrogen
atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or
10-membered heterocycloalkyl group optionally substituted with 1, 2
or 3 independently selected R.sup.h substituents;
[0134] or any two R.sup.c substituents together with the nitrogen
atom to which they are attached form a 4-, 5-, 6-, or 7-membered
heterocycloalkyl group optionally substituted with 1, 2, or 3
independently selected R.sup.h substituents;
[0135] or any two R.sup.e substituents together with the nitrogen
atom to which they are attached form a 4-, 5-, 6-, or 7-membered
heterocycloalkyl group optionally substituted with 1, 2, or 3
independently selected R.sup.h substituents;
[0136] or any two R.sup.g substituents together with the nitrogen
atom to which they are attached form a 4-, 5-, 6-, or 7-membered
heterocycloalkyl group optionally substituted with 1, 2, or 3
independently selected R.sup.h substituents;
[0137] each R.sup.h is independently selected from C.sub.1-6 alkyl,
C.sub.3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C.sub.6-10
aryl, 5-6 membered heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-4
alkyl-, (5-6 membered heteroaryl)-C.sub.1-4 alkyl-, (4-7 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, C.sub.1-6 haloalkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, halo, CN, OR.sup.i, C(O)R.sup.i,
C(O)NR.sup.iR.sup.i, C(O)OR.sup.i, OC(O)R.sup.i,
OC(O)NR.sup.iR.sup.i, NR.sup.iR.sup.i, NR.sup.iC(O)R.sup.i,
NR.sup.iC(O)NR.sup.iR.sup.i, NR.sup.iC(O)OR.sup.i, S(O)R.sup.i,
S(O)NR.sup.iR.sup.i, S(O).sub.2R.sup.i, NR.sup.iS(O).sub.2R.sup.i,
NR.sup.iS(O).sub.2NR.sup.iR.sup.i, and
S(O).sub.2NR.sup.iR.sup.i
[0138] each R.sup.i is independently selected from H, C.sub.1-4
alkyl, C.sub.3-6 cycloalkyl, C.sub.6-10 aryl, 5 or 6-membered
heteroaryl, C.sub.1-4 haloalkyl, C.sub.2-4 alkenyl, and C.sub.2-4
alkynyl;
[0139] each R.sup.q is independently selected from OH, CN, --COOH,
NH.sub.2, halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6
alkoxy, C.sub.1-6 haloalkoxy, C.sub.1-4 alkylthio, phenyl, 5-6
membered heteroaryl, C.sub.3-6 cycloalkyl, 4-6 membered
heterocycloalkyl, --CONHR.sup.12, --NHC(O)R.sup.2, --OC(O)R.sup.12,
--C(O)OR.sup.12, --C(O)R.sup.12, --SO.sub.2R.sup.12,
--NHSO.sub.2R.sup.12, --SO.sub.2NHR.sup.12 and NR.sup.12R.sup.12;
and
[0140] each R.sup.12 is independently C.sub.1-6 alkyl.
[0141] In some embodiments of the previous embodiment, one or more
hydrogen atoms can be replaced by deuterium atoms (e.g., one or
more hydrogen atoms of a C.sub.1-6 alkyl group can be replaced by
deuterium atoms).
[0142] In some embodiments:
[0143] X.sup.1 is N or CR.sup.1;
[0144] X.sup.2 is N or CR.sup.2;
[0145] X.sup.3 is N or CR.sup.3;
[0146] X.sup.4 is N or CR.sup.4;
[0147] X.sup.5 is N or CR.sup.5;
[0148] X.sup.6 is N or CR.sup.6;
[0149] X.sup.3, X.sup.4, X.sup.5 and X.sup.6 are not simultaneously
N;
[0150] R.sup.7 is H, methyl, or ethyl, wherein said methyl and
ethyl are each optionally substituted with 1, 2 or 3 groups
independently selected from halo, OH, oxo, CN, C.sub.1-6 haloalkyl,
C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, NH.sub.2, C.sub.1-6
alkyl-NH--, and (C.sub.1-6 alkyl).sub.2N--;
[0151] R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are
each independently selected from H, halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.1-6 haloalkoxy, C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10
membered heteroaryl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl-C.sub.1-4 alkyl-, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-,
(5-14 membered heteroaryl)-C.sub.1-4 alkyl-, (4-10 membered
heterocycloalkyl)-C.sub.14 alkyl-, CN, NO.sub.2, OR.sup.a1,
C(O)R.sup.a1, C(O)NR.sup.a1R.sup.a1, C(O)OR.sup.a1, OC(O)R.sup.a1,
OC(O)NR.sup.a1R.sup.a1, NR.sup.a1R.sup.a1, NR.sup.a1C(O)R.sup.a1
NR.sup.a1C(O)OR.sup.a1, NR.sup.a1C(O)NR.sup.a1R.sup.a1,
NR.sup.a1S(O)R.sup.a1, NR.sup.a1S(O).sub.2R.sup.a1,
NR.sup.a1S(O).sub.2NR.sup.a1R.sup.a1, S(O)R.sup.a1
S(O)NR.sup.a1R.sup.a1, S(O).sub.2R.sup.a1, and
S(O).sub.2NR.sup.a1R.sup.a1, wherein the C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, C.sub.3-10 cycloalkyl,
5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,
C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10 cycloalkyl-C.sub.1-4
alkyl-, (5-14 membered heteroaryl)-C.sub.1-4 alkyl-, and (4-10
membered heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.8 are each optionally
substituted with 1, 2, 3, 4 or 5 independently selected R.sup.b
substituents;
[0152] R.sup.3 is H, halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
C.sub.1-6alkoxy, C.sub.1-6 haloalkoxy, OH, CN, NH.sub.2, C.sub.1-6
alkyl-NH--, or (C.sub.1-6 alkyl).sub.2N--;
[0153] R.sup.9 is H, CN, NH.sub.2, --OH, --COOH, --NH(C.sub.1-6
alkyl), --NH(C.sub.1-6 alkyl).sub.2, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.1-6 alkoxy or C.sub.1-6 haloalkoxy, wherein the
C.sub.1-6 alkyl is optionally substituted with 1, 2 or 3
independently selected R.sup.q substituents;
[0154] R.sup.10 is selected from C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, C.sub.1-6
haloalkoxy, C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered
heteroaryl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl-C.sub.1-4 alkyl-, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-,
(5-14 membered heteroaryl)-C.sub.1-4 alkyl-, (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, OR.sup.a2, C(O)R.sup.a2,
C(O)NR.sup.a2R.sup.a2, C(O)OR.sup.a2, NR.sup.a2R.sup.a2,
NR.sup.a2C(O)R.sup.a2, NR.sup.a2C(O)OR.sup.a2,
NR.sup.a2C(O)NR.sup.a2R.sup.a2, NR.sup.a2S(O)R.sup.a2,
NR.sup.a2S(O).sub.2R.sup.a2, NR.sup.a2S(O).sub.2NR.sup.a2R.sup.a2,
S(O)R.sup.a2, S(O).sub.2R.sup.a2, wherein the C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.14 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-14 membered heteroaryl)-C.sub.1-4
alkyl-, and (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl- of
R.sup.10 are each optionally substituted with 1, 2, 3, 4 or 5
independently selected R.sup.b substituents;
[0155] L is
##STR00010##
or --SO.sub.2--, wherein each R.sup.11 is independently H or
C.sub.1-6 alkyl optionally substituted with 1 or 2 R.sup.q
substituents and wherein the single wavy line indicates the point
of attachment to R.sup.10 and the double wavy line indicates the
point of attachment to the 6-membered ring A;
[0156] R.sup.a1 and R.sup.a2 are each independently selected from
H, C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10
membered heteroaryl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl-C.sub.1-4 alkyl-, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-,
(5-10 membered heteroaryl)-C.sub.1-4 alkyl-, and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, wherein the C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered heteroaryl)-C.sub.1-4
alkyl- and (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl- of
R.sup.a1 and R.sup.a2 are each optionally substituted with 1, 2, 3,
4, or 5 independently selected R.sup.d substituents;
[0157] each R.sup.b substituent is independently selected from
halo, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered
heteroaryl)-C.sub.1-4 alkyl-, (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, CN, NO.sub.2, OR.sup.c,
C(O)R.sup.c, C(O)NR.sup.cR.sup.c, C(O)OR.sup.c, OC(O)R.sup.c,
OC(O)NR.sup.cR.sup.c, NR.sup.cR.sup.c, NR.sup.cC(O)R.sup.c,
NR.sup.cC(O)OR.sup.c, NR.sup.cC(O)NR.sup.cR.sup.c,
NR.sup.cS(O)R.sup.c, NR.sup.cS(O).sub.2R.sup.c,
NR.sup.cS(O).sub.2NR.sup.cR.sup.c, S(O)R.sup.c,
S(O)NR.sup.cR.sup.c, S(O).sub.2R.sup.c or
S(O).sub.2NR.sup.cR.sup.c; wherein the C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, C.sub.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered heteroaryl)-C.sub.1-4
alkyl-and (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl- of
R.sup.b are each further optionally substituted with 1, 2, or 3
independently selected R.sup.d substituents;
[0158] each R.sup.c is independently selected from H, C.sub.1-6
alkyl, C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered
heteroaryl)-C.sub.1-4 alkyl-, and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-;
[0159] each R.sup.d is independently selected from C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, halo, C.sub.3-10 cycloalkyl, C.sub.6-10 aryl,
5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,
C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10 cycloalkyl-C.sub.1-4
alkyl-, (5-10 membered heteroaryl)-C.sub.1-4 alkyl-, and (4-10
membered heterocycloalkyl)-C.sub.1-4 alkyl-, CN, OR.sup.e,
C(O)R.sup.e, C(O)NR.sup.eR.sup.e, C(O)OR.sup.e, OC(O)R.sup.e,
OC(O)NR.sup.eR.sup.e, NR.sup.eR.sup.e, NR.sup.eC(O)R.sup.e,
NR.sup.eC(O)NR.sup.eR.sup.e, NR.sup.eC(O)OR, S(O)R.sup.e,
S(O)NR.sup.eR.sup.e, S(O).sub.2R.sup.e, NR.sup.eS(O).sub.2R.sup.e,
NR.sup.eS(O).sub.2NR.sup.eR.sup.e, and
S(O).sub.2NR.sup.eR.sup.e;
[0160] each R.sup.e is independently selected from H, CN, C.sub.1-6
alkyl, C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered
heteroaryl)-C.sub.1-4 alkyl-, and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-;
[0161] or any two R.sup.a1 substituents together with the nitrogen
atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or
10-membered heterocycloalkyl group optionally substituted with 1, 2
or 3 independently selected R.sup.h substituents;
[0162] or any two R.sup.a2 substituents together with the nitrogen
atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or
10-membered heterocycloalkyl group optionally substituted with 1, 2
or 3 independently selected R.sup.h substituents;
[0163] or any two R.sup.c substituents together with the nitrogen
atom to which they are attached form a 4-, 5-, 6-, or 7-membered
heterocycloalkyl group optionally substituted with 1, 2, or 3
independently selected R.sup.h substituents;
[0164] or any two R.sup.e substituents together with the nitrogen
atom to which they are attached form a 4-, 5-, 6-, or 7-membered
heterocycloalkyl group optionally substituted with 1, 2, or 3
independently selected R.sup.h substituents;
[0165] or any two R.sup.g substituents together with the nitrogen
atom to which they are attached form a 4-, 5-, 6-, or 7-membered
heterocycloalkyl group optionally substituted with 1, 2, or 3
independently selected R.sup.h substituents;
[0166] each R.sup.h is independently selected from C.sub.1-6 alkyl,
C.sub.3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C.sub.6-10
aryl, 5-6 membered heteroaryl, C.sub.3-10 cycloalkyl-C.sub.1-4
alkyl-, (5-6 membered heteroaryl)-C.sub.1-4 alkyl-, (4-7 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, C.sub.1-6 haloalkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, halo, CN, OW, C(O)R,
C(O)NR.sup.iR.sup.i, C(O)OR.sup.i, OC(O)R.sup.i,
OC(O)NR.sup.iR.sup.i, NR.sup.iR.sup.i, NR.sup.iC(O)R.sup.i,
NR.sup.iC(O)NR.sup.iR.sup.i, NR.sup.iC(O)OR.sup.i, S(O)R.sup.i,
S(O)NR.sup.iR.sup.i, S(O).sub.2R.sup.i, NR.sup.iS(O).sub.2R.sup.i,
NR.sup.iS(O).sub.2NR.sup.iR.sup.i, and
S(O).sub.2NR.sup.iR.sup.i
[0167] each R.sup.i is independently selected from H, C.sub.1-4
alkyl, C.sub.3-6 cycloalkyl, C.sub.6-10 aryl, 5 or 6-membered
heteroaryl, C.sub.1-4 haloalkyl, C.sub.2-4 alkenyl, and C.sub.2-4
alkynyl;
[0168] each R.sup.q is independently selected from OH, CN, --COOH,
NH.sub.2, halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6
alkoxy, C.sub.1-6 haloalkoxy, C.sub.1-4 alkylthio, phenyl, 5-6
membered heteroaryl, C.sub.3-6 cycloalkyl, 4-6 membered
heterocycloalkyl, --CONHR.sup.12, --NHC(O)R.sup.12,
--OC(O)R.sup.12, --C(O)OR.sup.12, --C(O)R.sup.12,
--SO.sub.2R.sup.12, --NHSO.sub.2R.sup.12, --SO.sub.2NHR.sup.12 and
NR.sup.12R.sup.12; and
[0169] each R.sup.12 is independently C.sub.1-6 alkyl.
[0170] In some embodiments, one or more hydrogen atoms in a
compound of the present disclosure (e.g., a compound of Formula I,
II, III, IV, V, and the like), or a pharmaceutically acceptable
salt thereof, can be replaced by one or more deuterium atoms. In
some embodiments, one or more hydrogen atoms in a C.sub.1-6 alkyl
group can be replaced by deuterium atoms (e.g., --CD.sub.3).
[0171] In some embodiments, X.sup.1 is N.
[0172] In some embodiments, X.sup.1 is CR.sup.1.
[0173] In some embodiments, X.sup.2 is N.
[0174] In some embodiments, X.sup.2 is CR.sup.2.
[0175] In some embodiments, X.sup.3 is N.
[0176] In some embodiments, X.sup.3 is CR.sup.3.
[0177] In some embodiments, X.sup.4 is N.
[0178] In some embodiments, X.sup.4 is CR.sup.4.
[0179] In some embodiments, X.sup.4 is CH.
[0180] In some embodiments, X.sup.5 is N.
[0181] In some embodiments, X.sup.5 is CR.sup.5.
[0182] In some embodiments, X.sup.5 is CH.
[0183] In some embodiments, X.sup.4 is CH and X.sup.5 is CH or
N.
[0184] In some embodiments, X.sup.6 is N.
[0185] In some embodiments, X.sup.6 is CR.sup.6.
[0186] In some embodiments, R.sup.1 is H, halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.1-6 haloalkoxy, C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10
membered heteroaryl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl-C.sub.1-4 alkyl-, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-,
(5-14 membered heteroaryl)-C.sub.1-4 alkyl-, (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, wherein the C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-14 membered heteroaryl)-C.sub.1-4
alkyl-, and (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl- are
each optionally substituted by 1, 2, 3, 4, or 5 independently
selected R.sup.b substituents.
[0187] In some embodiments, R.sup.1 is H, halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.1-6 haloalkoxy, C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10
membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein
the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
and 4-10 membered heterocycloalkyl are each optionally substituted
by 1, 2, 3, 4, or 5 independently selected R.sup.b
substituents.
[0188] In some embodiments, R.sup.1 is H, halo, C.sub.6-10 aryl,
C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered
heterocycloalkyl, wherein the C.sub.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered
heterocycloalkyl are each optionally substituted by 1, 2, 3, 4, or
5 independently selected R.sup.b substituents.
[0189] In some embodiments, R.sup.1 is H, halo, or 5-10 membered
heteroaryl, wherein the 5-10 membered heteroaryl is optionally
substituted by 1, 2, 3, 4, or 5 independently selected R.sup.b
substituents.
[0190] In some embodiments, R.sup.1 is H, halo, or 5-10 membered
heteroaryl, wherein the 5-10 membered heteroaryl is optionally
substituted by 1 or 2 independently selected R.sup.b
substituents.
[0191] In some embodiments, R.sup.1 is H, halo, or 5-6 membered
heteroaryl, wherein the 5-6 membered heteroaryl is optionally
substituted by 1 or 2 independently selected R.sup.b
substituents.
[0192] In some embodiments, R.sup.1 is H, halo, or 5-6 membered
heteroaryl, wherein the 5-6 membered heteroaryl is optionally
substituted by 1 or 2 independently selected C.sub.1-4 alkyl
groups.
[0193] In some embodiments, R.sup.1 is H, Cl, or
1-methyl-1H-pyrazol-4-yl.
[0194] In some embodiments, R.sup.2 is H, halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, or C.sub.1-6 haloalkyl,
wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6
alkynyl are each optionally substituted with 1, 2, 3, 4 or 5
independently selected R.sup.b substituents.
[0195] In some embodiments, R.sup.2 is H.
[0196] In some embodiments, R.sup.3 is H, halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, or C.sub.1-6 haloalkyl,
wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6
alkynyl are each optionally substituted with 1, 2, 3, 4 or 5
independently selected R.sup.b substituents.
[0197] In some embodiments, R.sup.3 is H.
[0198] In some embodiments, R.sup.4 is H, halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, or C.sub.1-6 haloalkyl,
wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6
alkynyl are optionally substituted by 1, 2, 3, 4, or 5
independently selected R.sup.b substituents.
[0199] In some embodiments, R.sup.4 is H, halo, C.sub.1-6 alkyl, or
C.sub.1-6 haloalkyl, wherein the C.sub.1-6 alkyl is optionally
substituted by 1, 2, 3, 4, or 5 independently selected R.sup.b
substituents.
[0200] In some embodiments, R.sup.4 is H, halo, or C.sub.1-6 alkyl,
wherein the C.sub.1-6 alkyl is optionally substituted by 1, 2, 3,
4, or 5 independently selected R.sup.b substituents.
[0201] In some embodiments, R.sup.4 is H, D, F, Cl, CD.sub.3, or
methyl.
[0202] In some embodiments, R.sup.4 is H, F, Cl, CD.sub.3, or
methyl.
[0203] In some embodiments, R.sup.4 is H, F, CD.sub.3, or
methyl.
[0204] In some embodiments, R.sup.4 is H, F, or methyl.
[0205] In some embodiments, R.sup.4 is Cl, CD.sub.3, or methyl.
[0206] In some embodiments, R.sup.4 is CD.sub.3, or methyl.
[0207] In some embodiments, R.sup.5 is H, halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, or C.sub.1-6 haloalkyl,
wherein said C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6
alkynyl are each optionally substituted by 1, 2, 3, 4, or 5
independently selected R.sup.b substituents.
[0208] In some embodiments, R.sup.5 is H, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, or C.sub.1-6 haloalkyl,
wherein said C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6
alkynyl are each optionally substituted by 1, 2, 3, 4, or 5
independently selected R.sup.b substituents.
[0209] In some embodiments, R.sup.5 is H, halo, C.sub.1-6 alkyl, or
C.sub.1-6 haloalkyl, wherein the C.sub.1-6 alkyl is optionally
substituted by 1, 2, 3, 4, or 5 independently selected R.sup.b
substituents.
[0210] In some embodiments, R.sup.5 is H, C.sub.1-6 alkyl, or
C.sub.1-6 haloalkyl, wherein the C.sub.1-6 alkyl is optionally
substituted by 1, 2, 3, 4, or 5 independently selected R.sup.b
substituents.
[0211] In some embodiments, R.sup.5 is H or C.sub.1-6alkyl, wherein
the C.sub.1-6 alkyl is optionally substituted by 1, 2, 3, 4, or 5
independently selected R.sup.b substituents.
[0212] In some embodiments, R.sup.5 is H or C.sub.1-6 alkyl.
[0213] In some embodiments, R.sup.5 is H or methyl.
[0214] In some embodiments, R.sup.5 is H or F.
[0215] In some embodiments, R.sup.4 is H and R.sup.5 is H.
[0216] In some embodiments, R.sup.6 is H, halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, CN,
NO.sub.2, OR.sup.a1, SR.sup.a1, C(O)R.sup.a1,
C(O)NR.sup.a1R.sup.a1, C(O)OR.sup.a1, OC(O)R.sup.a1,
OC(O)NR.sup.a1R.sup.a1, NR.sup.a1R.sup.a1 NR.sup.a1C(O)R.sup.a1,
NR.sup.a1C(O)OR.sup.a1, NR.sup.a1C(O)NR.sup.a1R.sup.a1,
C(.dbd.NR.sup.a1)R.sup.a1, C(.dbd.NR.sup.a1)NR.sup.a1R.sup.a1,
NR.sup.a1C(.dbd.NR.sup.a1)NR.sup.a1R.sup.a1,
NR.sup.a1C(.dbd.NOH)NR.sup.a1R.sup.a1,
NR.sup.a1C(.dbd.NCN)NR.sup.a1R.sup.a1, NR.sup.a1S(O)R.sup.a1
NR.sup.a1S(O).sub.2R.sup.a1, NR.sup.a1S(O).sub.2NR.sup.a1R.sup.a1,
S(O)R.sup.a1, S(O)NR.sup.a1R.sup.a1, S(O).sub.2R.sup.a1, SF.sub.5,
--P(O)R.sup.a1R.sup.a1, --P(O)(OR.sup.a1)(OR.sup.a1) and
S(O).sub.2NR.sup.a1R.sup.a1, wherein the C.sub.1-6 alkyl, C.sub.2-6
alkenyl, and C.sub.2-6 alkynyl are optionally substituted by 1, 2,
3, 4, or 5 independently selected R.sup.b substituents.
[0217] In some embodiments, R.sup.6 is H, halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, CN,
NO.sub.2, OR.sup.a1, C(O)R.sup.a1, C(O)NR.sup.a1R.sup.a1,
C(O)OR.sup.a1, OC(O)R.sup.a1, OC(O)NR.sup.a1R.sup.a1,
NR.sup.a1R.sup.a1 NR.sup.a1C(O)R.sup.a1, NR.sup.a1C(O)OR.sup.a1,
NR.sup.a1C(O)NR.sup.a1R.sup.a1, NR.sup.a1S(O)R.sup.a1,
NR.sup.a1S(O).sub.2R.sup.a1, NR.sup.a1S(O).sub.2NR.sup.a1R.sup.a1,
S(O)R.sup.a1, S(O)NR.sup.a1R.sup.a1, S(O).sub.2R.sup.a1, and
S(O).sub.2NR.sup.a1R.sup.a1, wherein the C.sub.1-6 alkyl, C.sub.2-6
alkenyl, and C.sub.2-6 alkynyl are optionally substituted by 1, 2,
3, 4, or 5 independently selected R.sup.b substituents.
[0218] In some embodiments, R.sup.6 is H, halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
OR.sup.a1, SR.sup.a1, C(O)R.sup.a1, C(O)NR.sup.a1R.sup.a1,
C(O)OR.sup.a1, OC(O)R.sup.a1, or OC(O)NR.sup.a1R.sup.a1, wherein
the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are
optionally substituted by 1, 2, 3, 4, or 5 independently selected
R.sup.b substituents.
[0219] In some embodiments, R.sup.6 is H, halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, or
OR.sup.a, wherein said C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl are optionally substituted by 1, 2, 3, 4, or 5
independently selected R.sup.b substituents.
[0220] In some embodiments, R.sup.6 is H, halo, C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, or OR.sup.a1, wherein said C.sub.1-6 alkyl is
optionally substituted by 1, 2, 3, 4, or 5 independently selected
R.sup.b substituents.
[0221] In some embodiments, R.sup.6 is H, halo, C.sub.1-6 alkyl, or
OR.sup.a1, wherein said C.sub.1-6 alkyl is optionally substituted
by 1, 2, 3, 4, or 5 independently selected R.sup.b
substituents.
[0222] In some embodiments, R.sup.6 is H, halo, C.sub.1-6 alkyl, or
OR.sup.a1.
[0223] In some embodiments, R.sup.6 is H, F, Cl, methyl, methoxy,
or ethoxy.
[0224] In some embodiments, R.sup.6 is halo, C.sub.1-6 alkyl, or
CN.
[0225] In some embodiments, R.sup.7 is H or C.sub.1-6 alkyl
optionally substituted with 1, 2 or 3 groups independently selected
from halo, OH, oxo, CN, C.sub.1-6 alkoxy, and C.sub.1-6
haloalkoxy.
[0226] In some embodiments, R.sup.7 is H or C.sub.1-6 alkyl
optionally substituted with 1, 2 or 3 groups independently selected
from OH and oxo.
[0227] In some embodiments, R.sup.7 is H, unsubstituted C.sub.1-6
alkyl, or C.sub.1-6 alkyl substituted by oxo.
[0228] In some embodiments, R.sup.7 is H, unsubstituted C.sub.1-2
alkyl, or C.sub.1-6 alkyl substituted by oxo.
[0229] In some embodiments, R.sup.7 is H, methyl, or ethyl, wherein
said methyl or ethyl are optionally substituted with 1, 2 or 3
groups independently selected from halo, OH, oxo, CN, C.sub.1-6
alkoxy, and C.sub.1-6 haloalkoxy.
[0230] In some embodiments, R.sup.7 is H, methyl, or
C(.dbd.O)CH.sub.3.
[0231] In some embodiments, R.sup.7 is H.
[0232] In some embodiments, R.sup.8 is H, halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-14 membered
heteroaryl)-C.sub.1-4 alkyl-, or (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, wherein the C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-14 membered heteroaryl)-C.sub.1-4
alkyl-, and (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl- are
each optionally substituted with 1, 2, 3, 4 or 5 independently
selected R.sup.b substituents.
[0233] In some embodiments, R.sup.8 is H, halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-14 membered
heteroaryl)-C.sub.1-4 alkyl-, or (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, wherein the C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-14 membered heteroaryl)-C.sub.1-4
alkyl-, and (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl- are
each optionally substituted with 1, 2, or 3 independently selected
R.sup.q substituents.
[0234] In some embodiments, R.sup.8 is H, halo, C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10
membered heteroaryl, 4-10 membered heterocycloalkyl, C.sub.6-10
aryl-C14 alkyl-, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-14
membered heteroaryl)-C.sub.1-4 alkyl-, or (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, wherein the C.sub.1-6 alkyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-14 membered
heteroaryl)-C.sub.1-4 alkyl-, and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl- are each optionally substituted
with 1, 2, 3, 4 or 5 independently selected R.sup.b
substituents.
[0235] In some embodiments, R.sup.8 is H, halo, C.sub.1-6 alkyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-14 membered
heteroaryl)-C.sub.1-4 alkyl-, or (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, wherein the C.sub.1-6 alkyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-14 membered
heteroaryl)-C.sub.1-4 alkyl-, and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl- are each optionally substituted
with 1, 2, 3, 4 or 5 independently selected R.sup.b
substituents.
[0236] In some embodiments, R.sup.8 is H, halo, C.sub.1-6 alkyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-14 membered
heteroaryl)-C.sub.1-4 alkyl-, or (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, wherein the C.sub.1-6 alkyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-14 membered
heteroaryl)-C.sub.1-4 alkyl-, and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl- are each optionally substituted
with 1, 2, or 3 independently selected R.sup.q substituents.
[0237] In some embodiments, R.sup.8 is H, halo, C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
(5-10 membered heteroaryl)-C.sub.1-4 alkyl-, or (4-10 membered
heterocycloalkyl)-C.sub.14 alkyl-, wherein the C.sub.1-6 alkyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, (5-10 membered
heteroaryl)-C.sub.1-4 alkyl-, and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl- are each optionally substituted
with 1, 2, 3, 4 or 5 independently selected R.sup.b
substituents.
[0238] In some embodiments, R.sup.8 is H, halo, C.sub.1-6 alkyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, (5-10 membered
heteroaryl)-C.sub.1-4 alkyl-, or (4-10 membered
heterocycloalkyl)-C.sub.14 alkyl-, wherein the C.sub.1-6 alkyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, (5-10 membered
heteroaryl)-C.sub.1-4 alkyl-, and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl- are each optionally substituted
with 1, 2, 3, 4 or 5 independently selected R.sup.b
substituents.
[0239] In some embodiments, R.sup.8 is H, halo, C.sub.1-6 alkyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, (5-10 membered
heteroaryl)-C.sub.1-4 alkyl-, or (4-10 membered
heterocycloalkyl)-C.sub.14 alkyl-, wherein the C.sub.1-6 alkyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, (5-10 membered
heteroaryl)-C.sub.1-4 alkyl-, and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl- are each optionally substituted
with 1, 2, or 3 independently selected R.sup.q substituents.
[0240] In some embodiments, R.sup.8 is H, halo, C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, C.sub.3-6 cycloalkyl, phenyl, 5-6 membered
heteroaryl, or 5-6 membered heterocycloalkyl, wherein the C.sub.1-6
alkyl, phenyl, 5-6 membered heteroaryl, and 5-6 membered
heterocycloalkyl each optionally substituted with 1, 2, 3, 4 or 5
independently selected R.sup.b substituents.
[0241] In some embodiments, R.sup.8 is H, halo, C.sub.1-6 alkyl,
phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocycloalkyl,
wherein the C.sub.1-6 alkyl, phenyl, 5-6 membered heteroaryl, and
5-6 membered heterocycloalkyl each optionally substituted with 1,
2, 3, 4 or 5 independently selected R.sup.b substituents.
[0242] In some embodiments, R.sup.8 is H, halo, C.sub.1-6 alkyl,
phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocycloalkyl,
wherein the C.sub.1-6 alkyl, phenyl, 5-6 membered heteroaryl, and
5-6 membered heterocycloalkyl each optionally substituted with 1,
2, or 3 independently selected R.sup.g substituents.
[0243] In some embodiments, R.sup.8 is halo, C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, C.sub.3-6 cycloalkyl, C.sub.6-10 aryl or 5-6
membered heteroaryl, wherein C.sub.1-6 alkyl, C.sub.6-10 aryl and
5-6 membered heteroaryl are each optionally substituted with 1, 2
or 3 independently selected R.sup.b substituents.
[0244] In some embodiments, R.sup.8 is halo, C.sub.1-6 alkyl,
C.sub.6-10 aryl or 5-6 membered heteroaryl, wherein C.sub.1-6
alkyl, C.sub.6-10 aryl and 5-6 membered heteroaryl are each
optionally substituted with 1, 2 or 3 independently selected
R.sup.b substituents.
[0245] In some embodiments, R.sup.8 is halo, C.sub.1-6 alkyl,
C.sub.6-10 aryl or 5-6 membered heteroaryl, wherein C.sub.1-6
alkyl, C.sub.6-10 aryl and 5-6 membered heteroaryl are each
optionally substituted with 1, 2, or 3 independently selected
R.sup.q substituents.
[0246] In some embodiments, R.sup.8 is halo, C.sub.1-6alkyl,
C.sub.1-6 haloalkyl, C.sub.3-6 cycloalkyl, phenyl, or 5-6 membered
heteroaryl, wherein C.sub.1-6 alkyl, phenyl, and 5-6 membered
heteroaryl are each optionally substituted with 1, 2 or 3 R.sup.b
substituents.
[0247] In some embodiments, R.sup.8 is halo, C.sub.1-6 alkyl,
phenyl, or 5-6 membered heteroaryl, wherein C.sub.1-6 alkyl,
phenyl, and 5-6 membered heteroaryl are each optionally substituted
with 1, 2 or 3 R.sup.b substituents.
[0248] In some embodiments, R.sup.8 is halo, C.sub.1-6 alkyl,
phenyl, or 5-6 membered heteroaryl, wherein C.sub.1-6 alkyl,
phenyl, and 5-6 membered heteroaryl are each optionally substituted
with 1, 2, or 3 independently selected R.sup.q substituents.
[0249] In some embodiments, R.sup.8 is H, halo, C.sub.1-6 alkyl, or
C.sub.1-6 haloalkyl.
[0250] In some embodiments, R.sup.8 is H, halo, or C.sub.1-6
alkyl.
[0251] In some embodiments, R.sup.8 is H, Cl, F, Br, methyl, or
ethyl.
[0252] In some embodiments, R.sup.8 is phenyl, which is optionally
substituted with 1, 2, 3, 4 or 5 independently selected R.sup.b
substituents.
[0253] In some embodiments, R.sup.8 is phenyl, which is optionally
substituted with 1 or 2 independently selected R.sup.b
substituents.
[0254] In some embodiments, R.sup.8 is phenyl, which is optionally
substituted with 1, 2, or 3 independently selected R.sup.q
substituents.
[0255] In some embodiments, R.sup.8 is phenyl, which is optionally
substituted with 1 or 2 independently selected R.sup.b substituents
selected from halo, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, CN,
NO.sub.2, OR.sup.c, SR.sup.c, C(O)R.sup.c, C(O)NR.sup.cR.sup.c,
C(O)OR.sup.c, OC(O)R.sup.c, OC(O)NR.sup.cR.sup.c,
C(.dbd.NR.sup.c)NR.sup.cR.sup.c,
NR.sup.cC(.dbd.NR.sup.c)NR.sup.cR.sup.c,
NR.sup.cC(.dbd.NOH)NR.sup.cR.sup.c,
NR.sup.cC(.dbd.NCN)NR.sup.cR.sup.c, SF.sub.5, --P(O)R.sup.cR.sup.c,
--P(O)(OR.sup.c)(OR.sup.c), NR.sup.cR.sup.c, NR.sup.cC(O)R.sup.c,
NR.sup.cC(O)OR.sup.c, NR.sup.cC(O)NR.sup.cR.sup.c,
NR.sup.cS(O)R.sup.c, NR.sup.cS(O).sub.2R.sup.c,
NR.sup.cS(O).sub.2NR.sup.cR.sup.c, S(O)R.sup.c,
S(O)NR.sup.cR.sup.c, S(O).sub.2R.sup.c and
S(O).sub.2NR.sup.cR.sup.c.
[0256] In some embodiments, R.sup.8 is phenyl, which is optionally
substituted with 1 or 2 independently selected R.sup.b substituents
independently selected from halo, C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, CN, NO.sub.2, OR.sup.c, SR.sup.c, C(O)R.sup.c,
C(O)NR.sup.cR.sup.c, C(O)OR.sup.c, OC(O)R.sup.c,
OC(O)NR.sup.cR.sup.c, NR.sup.cR.sup.c, NR.sup.cC(O)R.sup.c,
NR.sup.cC(O)OR.sup.c, NR.sup.cC(O)NR.sup.cR.sup.c,
NR.sup.cS(O)R.sup.c, NR.sup.cS(O).sub.2R.sup.c,
NR.sup.cS(O).sub.2NR.sup.cR.sup.c, S(O)R.sup.c,
S(O)NR.sup.cR.sup.c, S(O).sub.2R.sup.c and
S(O).sub.2NR.sup.cR.sup.c.
[0257] In some embodiments, R.sup.8 is phenyl, which is optionally
substituted with 1 or 2 independently selected R.sup.b substituents
independently selected from halo, C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, CN, NR.sup.cR.sup.c, NO.sub.2, OR.sup.c, S(O)R.sup.c,
S(O).sub.2R.sup.c, and S(O).sub.2NR.sup.cR.sup.c.
[0258] In some embodiments, R.sup.8 is phenyl, which is optionally
substituted with 1 or 2 independently selected R.sup.b substituents
independently selected from halo, C.sub.1-4 alkyl, CN, OR.sup.c,
and S(O).sub.2R.sup.c.
[0259] In some embodiments, R.sup.8 is phenyl, which is optionally
substituted with 1 or 2 independently selected R.sup.b substituents
independently selected from halo, C.sub.1-4 alkyl, CN, OR.sup.c,
and S(O).sub.2R.sup.c, wherein each R.sup.c is an independently
selected C.sub.1-6 alkyl group.
[0260] In some embodiments, R.sup.8 is phenyl, 2-methylphenyl,
3-methylphenyl, 4-methylphenyl, 2-fluorophenyl, 3-fluorophenyl,
4-fluorophenyl, 4-cyanophenyl, or 2-fluoro-3-methoxyphenyl.
[0261] In some embodiments, R.sup.8 is a 5-6 membered heteroaryl or
5-6 membered heterocycloalkyl, wherein the 5-6 membered heteroaryl
and 5-6 membered heterocycloalkyl are each optionally substituted
with 1, 2, 3, 4 or 5 independently selected R.sup.b
substituents.
[0262] In some embodiments, R.sup.8 is a 5-6 membered heteroaryl,
which is optionally substituted with 1, 2, 3, 4 or 5 independently
selected R.sup.b substituents.
[0263] In some embodiments, R.sup.8 is a 5-6 membered heteroaryl,
which is optionally substituted with 1 or 2 independently selected
R.sup.b substituents.
[0264] In some embodiments, R.sup.8 is a 5-6 membered heteroaryl,
which is optionally substituted with 1 or 2 independently selected
R.sup.b substituents selected from halo, C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, CN, NO.sub.2, OR, SR.sup.c, C(O)R.sup.c,
C(O)NR.sup.cR.sup.c, C(O)OR.sup.c, OC(O)R.sup.c,
OC(O)NR.sup.cR.sup.c, C(.dbd.NR.sup.c)NR.sup.cR.sup.c,
NR.sup.cC(.dbd.NR.sup.c)NR.sup.cR.sup.c,
NR.sup.cC(.dbd.NOH)NR.sup.cR.sup.c,
NR.sup.cC(.dbd.NCN)NR.sup.cR.sup.c, SF.sub.5, --P(O)R.sup.cR.sup.c,
--P(O)(OR.sup.c)(OR.sup.c), NR.sup.cR.sup.c, NR.sup.cC(O)R.sup.c,
NR.sup.cC(O)OR.sup.c, NR.sup.cC(O)NR.sup.cR.sup.c,
NR.sup.cS(O)R.sup.c, NR.sup.cS(O).sub.2R.sup.c,
NR.sup.cS(O).sub.2NR.sup.cR.sup.c, S(O)R.sup.c,
S(O)NR.sup.cR.sup.c, S(O).sub.2R.sup.c and
S(O).sub.2NR.sup.cR.sup.c.
[0265] In some embodiments, R.sup.8 is a 5-6 membered heteroaryl,
which is optionally substituted with 1 or 2 independently selected
R.sup.b substituents selected from halo, C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, CN, NO.sub.2, OR, SR.sup.c, C(O)R.sup.c,
C(O)NR.sup.cR.sup.c, C(O)OR.sup.c, OC(O)R.sup.c,
OC(O)NR.sup.cR.sup.c, NR.sup.cR.sup.c, NR.sup.cC(O)R.sup.c,
NR.sup.cC(O)OR.sup.c, NR.sup.cC(O)NR.sup.cR.sup.c,
NR.sup.cS(O)R.sup.c, NR.sup.cS(O).sub.2R.sup.c,
NR.sup.cS(O).sub.2NR.sup.cR.sup.c, S(O)R.sup.c,
S(O)NR.sup.cR.sup.c, S(O).sub.2R.sup.c and
S(O).sub.2NR.sup.cR.sup.c.
[0266] In some embodiments, R.sup.8 is a 5-6 membered heteroaryl,
which is optionally substituted with 1 or 2 independently selected
R.sup.b substituents selected from halo, C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, CN, NR.sup.cR.sup.c, NO.sub.2, OR.sup.c, S(O)R.sup.c,
S(O).sub.2R.sup.c, and S(O).sub.2NR.sup.cR.sup.c.
[0267] In some embodiments, R.sup.8 is a 5-6 membered heteroaryl,
which is optionally substituted with 1 or 2 independently selected
R.sup.b substituents selected from C.sub.1-4 alkyl and C.sub.1-4
haloalkyl.
[0268] In some embodiments, R.sup.8 is a 5-6 membered heteroaryl,
which is optionally substituted with 1 or 2 independently selected
R.sup.b substituents selected from C.sub.1-4 alkyl.
[0269] In some embodiments, R.sup.8 is 2-fluoro-pyridin-3-yl,
pyridin-4-yl, 2-thienyl, 2-fluoro-5-(N-methylaminocarbonyl)phenyl,
3-methylsulfonylphenyl, 2-fluoro-6-methoxyphenyl,
1-methyl-1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-5-yl, pyrimidin-5-yl,
or 2-methylthiazol-5-yl.
[0270] In some embodiments, R.sup.8 is H, Br, Cl, C.sub.1-4 alkyl,
phenyl, 1H-pyrazol-3-yl, 1H-pyrazol-5-yl, 1H-pyrazol-4-yl,
1-methyl-1H-pyrazol-5-yl, 1-methyl-1H-pyrazol-4-yl, thiazol-2-yl,
thiazol-4-yl, thiazol-5-yl, pyridyl, thiophenyl or pyrimidinyl,
wherein the phenyl, 1H-pyrazol-3-yl, 1H-pyrazol-5-yl,
1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-5-yl,
1-methyl-1H-pyrazol-4-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl,
pyridyl, thiophenyl and pyrimidinyl are each optionally substituted
with 1 or 2 substituents independently selected from halo, CN,
--S(O).sub.2--C.sub.1-6 alkyl, C.sub.1-6 alkyl, and --C.sub.1-6
alkylene-OH.
[0271] In some embodiments, R.sup.8 is H, Br, Cl, C.sub.1-4 alkyl,
phenyl, 1H-pyrazol-5-yl, 1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-5-yl,
1-methyl-1H-pyrazol-4-yl, thiazol-5-yl, pyridyl, thiophenyl or
pyrimidinyl, wherein the phenyl, 1H-pyrazol-5-yl, 1H-pyrazol-4-yl,
1-methyl-1H-pyrazol-5-yl, 1-methyl-1H-pyrazol-4-yl, thiazol-5-yl,
pyridyl, thiophenyl and pyrimidinyl are each optionally substituted
with 1 or 2 substituents independently selected from halo, CN,
--S(O).sub.2--C.sub.1-6 alkyl, C.sub.1-6 alkyl, and --C.sub.1-6
alkylene-OH.
[0272] In some embodiments, R.sup.8 is H, Br, Cl, C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, cyclopropyl, phenyl, 1H-pyrazol-5-yl,
1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-5-yl,
1-methyl-1H-pyrazol-4-yl, thiazol-5-yl, isoxazol-4-yl,
isoxazol-5-yl, pyridyl, thiophenyl or pyrimidinyl, wherein the
C.sub.1-4 alkyl, phenyl, 1H-pyrazol-5-yl, 1H-pyrazol-4-yl,
1-methyl-1H-pyrazol-5-yl, 1-methyl-1H-pyrazol-4-yl, thiazol-5-yl,
isoxazol-4-yl, isoxazol-5-yl, pyridyl, thiophenyl and pyrimidinyl
are each optionally substituted with 1 or 2 independently selected
R.sup.b substituents.
[0273] In some embodiments, R.sup.8 is H, Br, Cl, C.sub.1-4 alkyl,
phenyl, 1H-pyrazol-5-yl, 1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-5-yl,
1-methyl-1H-pyrazol-4-yl, thiazol-5-yl, pyridyl, thiophenyl or
pyrimidinyl, wherein the phenyl, 1H-pyrazol-5-yl, 1H-pyrazol-4-yl,
1-methyl-1H-pyrazol-5-yl, 1-methyl-1H-pyrazol-4-yl, thiazol-5-yl,
pyridyl, thiophenyl and pyrimidinyl are each optionally substituted
with 1 or 2 independently selected R.sup.b substituents.
[0274] In some embodiments, R.sup.8 is H, Br, Cl, C.sub.1-4 alkyl,
phenyl, 1H-pyrazol-5-yl, 1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-5-yl,
1-methyl-1H-pyrazol-4-yl, thiazol-5-yl, pyridyl, thiophenyl or
pyrimidinyl, wherein the phenyl, 1H-pyrazol-5-yl, 1H-pyrazol-4-yl,
1-methyl-1H-pyrazol-5-yl, 1-methyl-1H-pyrazol-4-yl, thiazol-5-yl,
pyridyl, thiophenyl and pyrimidinyl are each optionally substituted
with 1 or 2 independently selected R.sup.b substituents.
[0275] In some embodiments, R.sup.8 is H, D, CD.sub.3, CF.sub.3,
methyl, C(O)NR.sup.a1R.sup.a1, C.sub.3-6 cycloalkyl, C6-10 aryl, or
4-10 membered heterocycloalkyl, wherein the C.sub.6-10 aryl and
4-10 membered heterocycloalkyl are each optionally substituted with
1 or 2 independently selected R.sup.b substituents.
[0276] In some embodiments, R.sup.8 is H, D, CD.sub.3, CF.sub.3,
methyl, C(O)NR.sup.a1R.sup.a1, cyclopropyl, phenyl,
1H-pyrazol-5-yl, 1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-5-yl,
1-methyl-1H-pyrazol-4-yl, thiazol-5-yl, isoxazol-4-yl,
isoxazol-5-yl, pyridyl, thiophenyl or pyrimidinyl, wherein the
phenyl, 1H-pyrazol-5-yl, 1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-5-yl,
1-methyl-1H-pyrazol-4-yl, thiazol-5-yl, isoxazol-4-yl,
isoxazol-5-yl, pyridyl, thiophenyl and pyrimidinyl are each
optionally substituted with 1 or 2 independently selected R.sup.b
substituents.
[0277] In some embodiments, R.sup.8 is H, D, CD.sub.3, CF.sub.3,
methyl, C(O)NR.sup.a1R.sup.a1, cyclopropyl, phenyl,
1H-pyrazol-5-yl, 1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-5-yl,
1-methyl-1H-pyrazol-4-yl, thiazol-5-yl, isoxazol-4-yl,
isoxazol-5-yl, pyridyl, thiophenyl or pyrimidinyl, wherein the
phenyl, 1H-pyrazol-5-yl, 1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-5-yl,
1-methyl-1H-pyrazol-4-yl, thiazol-5-yl, isoxazol-4-yl,
isoxazol-5-yl, pyridyl, thiophenyl and pyrimidinyl are each
optionally substituted with 1 or 2 independently selected R.sup.b
substituents.
[0278] In some embodiments, R.sup.8 is H, D, CD.sub.3, CF.sub.3,
methyl, C(O)NR.sup.a1R.sup.a1, C.sub.3-6 cycloalkyl, C6-10 aryl, or
4-10 membered heterocycloalkyl, wherein the C.sub.6-10 aryl and
4-10 membered heterocycloalkyl are each optionally substituted with
1 or 2 independently selected R substituents.
[0279] In some embodiments, R.sup.8 is H, CF.sub.3, or methyl.
[0280] In some embodiments, R.sup.g is H, halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, wherein
the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl, are
each optionally substituted with 1, 2, 3, 4 or 5 independently
selected R.sup.b substituents.
[0281] In some embodiments, R.sup.9 is H.
[0282] In some embodiments, R.sup.2 and R.sup.3 are each H.
[0283] In some embodiments, R.sup.2 and R.sup.9 are each H.
[0284] In some embodiments, R.sup.3 and R.sup.9 are each H.
[0285] In some embodiments, R.sup.2, R.sup.3, and R.sup.9 are each
H.
[0286] In some embodiments, R.sup.10 is H, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-14 membered
heteroaryl)-C.sub.1-4 alkyl-, or (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, wherein the C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-14 membered heteroaryl)-C.sub.1-4
alkyl-, and (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl- are
each optionally substituted with 1, 2, 3, 4 or 5 independently
selected R.sup.b substituents.
[0287] In some embodiments, R.sup.10 is C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, C.sub.6-10 aryl,
C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-14 membered heteroaryl)-C.sub.1-4
alkyl-, or (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl-,
wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-14 membered
heteroaryl)-C.sub.1-4 alkyl-, and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl- are each optionally substituted
with 1, 2, 3, 4 or 5 independently selected R.sup.b
substituents.
[0288] In some embodiments, R.sup.10 is C.sub.1-6 alkyl, C.sub.6-10
aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10
membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-14 membered
heteroaryl)-C.sub.1-4 alkyl-, or (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, wherein the C.sub.1-6 alkyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-14 membered
heteroaryl)-C.sub.1-4 alkyl-, and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl- are each optionally substituted
with 1, 2, 3, 4 or 5 independently selected R.sup.b
substituents.
[0289] In some embodiments, R.sup.10 is C.sub.1-6 alkyl, phenyl,
C.sub.3-6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered
heterocycloalkyl, phenyl-C.sub.1-4 alkyl-, C.sub.3-6
cycloalkyl-C.sub.1-4 alkyl-, (5-6 membered heteroaryl)-C.sub.1-4
alkyl-, or (4-6 membered heterocycloalkyl)-C.sub.1-4 alkyl-,
wherein the C.sub.1-6 alkyl, phenyl, C.sub.3-6 cycloalkyl, 5-6
membered heteroaryl, 4-6 membered heterocycloalkyl,
phenyl-C.sub.1-4 alkyl-, C.sub.3-6 cycloalkyl-C.sub.1-4 alkyl-,
(5-6 membered heteroaryl)-C.sub.1-4 alkyl-, and (4-6 membered
heterocycloalkyl)-C.sub.1-4 alkyl- are each optionally substituted
with 1, 2, 3, 4 or 5 independently selected R.sup.b
substituents.
[0290] In some embodiments, R.sup.10 is C.sub.1-6 alkyl, C.sub.3-6
cycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-4 alkyl-, 4-6 membered
heterocycloalkyl or 4-6 membered heterocycloalkyl-C.sub.1-4 alkyl-,
each of which is optionally substituted with 1, 2 or 3
independently selected R.sup.b substituents.
[0291] In some embodiments, R.sup.10 is C.sub.1-6 alkyl, C.sub.3-6
cycloalkyl, 4-6 membered heterocycloalkyl, or (4-6 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, wherein the C.sub.1-6 alkyl,
phenyl, C.sub.3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and
(4-6 membered heterocycloalkyl)-C.sub.1-4 alkyl- are each
optionally substituted with 1, 2, 3, 4 or 5 independently selected
R.sup.b substituents.
[0292] In some embodiments, R.sup.10 is C.sub.1-6 alkyl, which is
optionally substituted with 1, 2, 3, 4 or 5 independently selected
R.sup.b substituents.
[0293] In some embodiments, R.sup.10 is C.sub.1-6 alkyl, which is
optionally substituted with 1 or 2 independently selected R.sup.b
substituents.
[0294] In some embodiments, R.sup.10 is C.sub.1-6 alkyl, which is
optionally substituted with 1 or 2 independently selected R.sup.b
substituents selected from halo, CN, NO.sub.2, OR, SR.sup.c, and
NR.sup.cR.sup.c.
[0295] In some embodiments, R.sup.10 is methyl, ethyl, or
3-hydroxypropyl.
[0296] In some embodiments, R.sup.10 is C.sub.3-10 cycloalkyl,
which is optionally substituted with 1, 2, 3, 4 or 5 independently
selected R.sup.b substituents.
[0297] In some embodiments, R.sup.10 is C.sub.3-6 cycloalkyl, which
is optionally substituted with 1 or 2 independently selected
R.sup.b substituents.
[0298] In some embodiments, R.sup.10 is C.sub.3-6 cycloalkyl, which
is optionally substituted with 1 or 2 independently selected
R.sup.b substituents selected from C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, CN, NO.sub.2, OR, SR.sup.c, C(O)R.sup.c,
C(O)NR.sup.cR.sup.c, C(O)OR.sup.c, OC(O)R.sup.c,
OC(O)NR.sup.cR.sup.c, C(.dbd.NR.sup.c)NR.sup.cR.sup.c,
NR.sup.cC(.dbd.NR.sup.c)NR.sup.cR.sup.c,
NR.sup.cC(.dbd.NOH)NR.sup.cR.sup.c,
NR.sup.cC(.dbd.NCN)NR.sup.cR.sup.c, SF.sub.5, --P(O)R.sup.cR.sup.c,
--P(O)(OR.sup.c)(OR.sup.c), NR.sup.cR.sup.c, NR.sup.cC(O)R.sup.c,
NR.sup.cC(O)OR.sup.c, NR.sup.cC(O)NR.sup.cR.sup.c,
NR.sup.cS(O)R.sup.c, NR.sup.cS(O).sub.2R.sup.c,
NR.sup.cS(O).sub.2NR.sup.cR.sup.c, S(O)R.sup.c,
S(O)NR.sup.cR.sup.c, S(O).sub.2R.sup.c and
S(O).sub.2NR.sup.cR.sup.c; wherein the C.sub.1-4 alkyl of R.sup.c
is further optionally substituted with 1, 2, or 3 independently
selected R.sup.d substituents selected from OR.sup.c.
[0299] In some embodiments, R.sup.10 is C.sub.3-6 cycloalkyl, which
is optionally substituted with 1 or 2 independently selected
R.sup.b substituents selected from C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, CN, NO.sub.2, OR, C(O)R.sup.c, C(O)NR.sup.cR.sup.c,
C(O)OR.sup.c, OC(O)R.sup.c, OC(O)NR.sup.cR.sup.c, NR.sup.cR.sup.c,
NR.sup.cC(O)R.sup.c, NR.sup.cC(O)OR.sup.c,
NR.sup.cC(O)NR.sup.cR.sup.c, NR.sup.cS(O)R.sup.c,
NR.sup.cS(O).sub.2R.sup.c, NR.sup.cS(O).sub.2NR.sup.cR.sup.c,
S(O)R.sup.c, S(O)NR.sup.cR.sup.c, S(O).sub.2R.sup.c and
S(O).sub.2NR.sup.cR.sup.c; wherein the C.sub.1-4 alkyl of R.sup.c
is further optionally substituted with 1, 2, or 3 independently
selected R.sup.d substituents selected from OR.sup.e.
[0300] In some embodiments, R.sup.10 is C.sub.3-6 cycloalkyl, which
is optionally substituted with 1 or 2 independently selected
R.sup.b substituents selected from C.sub.1-4 alkyl, OR.sup.a,
NR.sup.cR.sup.c, NR.sup.cC(O)R.sup.c, and NR.sup.cC(O)OR.sup.c,
wherein the C.sub.1-4 alkyl of R.sup.b is further optionally
substituted with 1, 2, or 3 independently selected R.sup.d
substituents selected from OR.sup.e.
[0301] In some embodiments, R.sup.10 is C.sub.3-6 cycloalkyl, which
is optionally substituted with 1 or 2 independently selected
R.sup.b substituents selected from C.sub.1-4 alkyl, OH, NH.sub.2,
NHC(O)R.sup.c, and NHC(O)OR.sup.c, wherein the C.sub.1-4 alkyl is
optionally substituted by OH, and each R.sup.c is an independently
selected C.sub.1-6 alkyl group.
[0302] In some embodiments, R.sup.10 is cyclopropyl,
3-hydroxycyclobutyl, 3-(hydroxymethyl)cyclobutyl,
4-hydroxycyclohexyl, 4-methoxycyclohexyl, 4-aminocyclohexyl,
4-(N-(tert butoxycarbonyl)amino)cyclohexyl, or
4-(N-(methylcarbonyl)amino)cyclohexyl.
[0303] In some embodiments, R.sup.10 is 4-10 membered
heterocycloalkyl, or (4-15 membered heterocycloalkyl)-C.sub.1-4
alkyl-, wherein the 4-10 membered heterocycloalkyl and (4-15
membered heterocycloalkyl)-C.sub.1-4 alkyl- are each optionally
substituted with 1, 2, 3, 4 or 5 independently selected R.sup.b
substituents.
[0304] In some embodiments, R.sup.10 is 4-10 membered
heterocycloalkyl, or (4-10 membered heterocycloalkyl)-C.sub.1-4
alkyl-, wherein the 4-10 membered heterocycloalkyl and (4-10
membered heterocycloalkyl)-C.sub.1-4 alkyl- are each optionally
substituted with 1, 2, 3, 4 or 5 independently selected R.sup.b
substituents.
[0305] In some embodiments, R.sup.10 is 4-10 membered
heterocycloalkyl, or (4-10 membered heterocycloalkyl)-C.sub.1-4
alkyl-, wherein the 4-10 membered heterocycloalkyl and (4-10
membered heterocycloalkyl)-C.sub.1-4 alkyl- are each optionally
substituted with 1, 2, or 3 independently selected R substituents
selected from C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, CN, NO.sub.2,
OR.sup.c, C(O)R.sup.c, C(O)NR.sup.cR.sup.c, C(O)OR.sup.c,
OC(O)R.sup.c, OC(O)NR.sup.cR.sup.c, NR.sup.cR.sup.c,
NR.sup.cC(O)R.sup.c, NR.sup.cC(O)OR.sup.c,
NR.sup.cC(O)NR.sup.cR.sup.c, NR.sup.cS(O)R.sup.c,
NR.sup.cS(O).sub.2R.sup.c, NR.sup.cS(O).sub.2NR.sup.cR.sup.c,
S(O)R.sup.c, S(O)NR.sup.cR.sup.c, S(O).sub.2R.sup.c and
S(O).sub.2NR.sup.cR.sup.c, wherein each C.sub.1-4 alkyl of R.sup.c
is further optionally substituted with 1, 2, or 3 independently
selected R.sup.d substituents.
[0306] In some embodiments, R.sup.10 is 4-6 membered
heterocycloalkyl or (4-6 membered heterocycloalkyl)-C.sub.1-4
alkyl-, wherein the 4-6 membered heterocycloalkyl and (4-6 membered
heterocycloalkyl)-C.sub.1-4 alkyl- are each optionally substituted
with 1, 2, 3, 4 or 5 independently selected R.sup.b
substituents.
[0307] In some embodiments, R.sup.10 is 4-6 membered
heterocycloalkyl or (4-6 membered heterocycloalkyl)-C.sub.1-4
alkyl-, wherein the 4-6 membered heterocycloalkyl and (4-6 membered
heterocycloalkyl)-C.sub.1-4 alkyl- are each optionally substituted
with 1 or 2 independently selected R.sup.b substituents selected
from C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, CN, NO.sub.2, OR,
SR.sup.c, C(O)R.sup.c, C(O)NR.sup.cR.sup.c, C(O)OR.sup.c,
OC(O)R.sup.c, OC(O)NR.sup.cR.sup.c,
C(.dbd.NR.sup.c)NR.sup.cR.sup.c,
NR.sup.cC(.dbd.NR.sup.c)NR.sup.cR.sup.c,
NR.sup.cC(.dbd.NOH)NR.sup.cR.sup.c,
NR.sup.cC(.dbd.NCN)NR.sup.cR.sup.c, SF.sub.5, --P(O)R.sup.cR.sup.c,
--P(O)(OR.sup.c)(OR.sup.c), NR.sup.cR.sup.c, NR.sup.cC(O)R.sup.c,
NR.sup.cC(O)OR.sup.c, NR.sup.cC(O)NR.sup.cR.sup.c,
NR.sup.cS(O)R.sup.c, NR.sup.cS(O).sub.2R.sup.c,
NR.sup.cS(O).sub.2NR.sup.cR.sup.c, S(O)R.sup.c,
S(O)NR.sup.cR.sup.c, S(O).sub.2R.sup.c and
S(O).sub.2NR.sup.cR.sup.c, wherein the C.sub.1-4 alkyl of R.sup.c
is further optionally substituted with 1, 2, or 3 independently
selected R.sup.d substituents.
[0308] In some embodiments, R.sup.10 is 4-6 membered
heterocycloalkyl or (4-6 membered heterocycloalkyl)-C.sub.1-4
alkyl-, wherein the 4-6 membered heterocycloalkyl and (4-6 membered
heterocycloalkyl)-C.sub.1-4 alkyl- are each optionally substituted
with 1 or 2 independently selected R.sup.b substituents selected
from C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, CN, NO.sub.2, OR.sup.c,
C(O)R.sup.c, C(O)NR.sup.cR.sup.c, C(O)OR.sup.c, OC(O)R.sup.c,
OC(O)NR.sup.cR.sup.c, NR.sup.cR.sup.c, NR.sup.cC(O)R.sup.c,
NR.sup.cC(O)OR.sup.c, NR.sup.cC(O)NR.sup.cR.sup.c,
NR.sup.cS(O)R.sup.c, NR.sup.cS(O).sub.2R.sup.c,
NR.sup.cS(O).sub.2NR.sup.cR.sup.c, S(O)R.sup.c,
S(O)NR.sup.cR.sup.c, S(O).sub.2R.sup.c and
S(O).sub.2NR.sup.cR.sup.c, wherein the C.sub.1-4 alkyl of R.sup.c
is further optionally substituted with 1, 2, or 3 independently
selected R.sup.d substituents.
[0309] In some embodiments, R.sup.10 is 4-6 membered
heterocycloalkyl or (4-6 membered heterocycloalkyl)-C.sub.1-4
alkyl-, wherein the 4-6 membered heterocycloalkyl and (4-6 membered
heterocycloalkyl)-C.sub.1-4 alkyl- are each optionally substituted
with 1 or 2 independently selected R.sup.b substituents selected
from C.sub.1-4 alkyl, OR.sup.a, NR.sup.cR.sup.c,
NR.sup.cC(O)R.sup.c, and NR.sup.cC(O)OR.sup.c, wherein the
C.sub.1-4 alkyl of R.sup.b is further optionally substituted with
1, 2, or 3 independently selected R.sup.d substituents.
[0310] In some embodiments, R.sup.10 is 4-6 membered
heterocycloalkyl, or (4-6 membered heterocycloalkyl)-C.sub.1-4
alkyl-, wherein the 4-6 membered heterocycloalkyl and (4-6 membered
heterocycloalkyl)-C.sub.1-4 alkyl- are each optionally substituted
with 1 or 2 independently selected R substituents selected from
C.sub.1-4 alkyl and OR.sup.a1, wherein the C.sub.1-4 alkyl of
R.sup.b is further optionally substituted with 1, 2, or 3
independently selected R.sup.d substituents selected from
OR.sup.c.
[0311] In some embodiments, R.sup.10 is 4-6 membered
heterocycloalkyl, or (4-6 membered heterocycloalkyl)-C.sub.1-4
alkyl-, wherein the 4-6 membered heterocycloalkyl and (4-6 membered
heterocycloalkyl)-C.sub.1-4 alkyl- are each optionally substituted
with 1 or 2 independently selected R.sup.b substituents selected
from C.sub.1-4 alkyl and OH, wherein the C.sub.1-4 alkyl is
optionally substituted by OH.
[0312] In some embodiments, R.sup.10 is tetrahydro-2H-pyran-4-yl,
4-hydroxypiperidin-1-yl, or
2-(hydroxymethyl)tetrahydro-1H-pyran-5-yl.
[0313] In some embodiments, R.sup.10 is methyl, ethyl,
3-hydroxypropyl, tetrahydrofuran-3-ylmethyl,
2-(3-oxetanyl)prop-1-yl, cyclopropyl, 3-hydroxycyclobutyl,
3-(hydroxymethyl)cyclobutyl, 4-hydroxycyclohexyl,
4-methoxycyclohexyl, 4-aminocyclohexyl, tetrahydro-2H-pyran-4-yl,
4-hydroxypiperidin-1-yl, 4-(N-(tert
butoxycarbonyl)amino)cyclohexyl,
4-(N-(methylcarbonyl)amino)cyclohexyl, or
2-(hydroxymethyl)tetrahydro-1H-pyran-5-yl, each of which is
optionally substituted with 1, 2 or 3 independently selected
R.sup.g substituents.
[0314] In some embodiments, R.sup.10 is methyl, ethyl,
3-hydroxypropyl, tetrahydrofuran-3-ylmethyl,
2-(3-oxetanyl)prop-1-yl, cyclopropyl, 3-hydroxycyclobutyl,
3-(hydroxymethyl)cyclobutyl, 4-hydroxycyclohexyl,
4-methoxycyclohexyl, 4-aminocyclohexyl, tetrahydro-2H-pyran-4-yl,
4-hydroxypiperidin-1-yl, 4-(N-(tert
butoxycarbonyl)amino)cyclohexyl,
4-(N-(methylcarbonyl)amino)cyclohexyl, or
2-(hydroxymethyl)tetrahydro-1H-pyran-5-yl.
[0315] In some embodiments, R.sup.10 is methyl, ethyl, propyl,
cyclopropyl, cyclobutyl, cyclohexyl, tetrahydrofuranyl,
tetrahydropyranyl, or --CH.sub.2-oxetanyl, each of which is
optionally substituted with 1 or 2 independently selected R.sup.b
substituents In some embodiments, R.sup.10 is methyl, ethyl,
propyl, cyclopropyl, cyclobutyl, cyclohexyl, tetrahydrofuranyl,
tetrahydropyranyl, or --CH.sub.2-oxetanyl, each of which is
optionally substituted with 1 or 2 independently selected R.sup.g
substituents.
[0316] In some embodiments, R.sup.10 is a bicyclic C.sub.4-10
cycloalkyl or a bicyclic 4-10 membered heterocycloalkyl, each of
which is optionally substituted with 1, 2, 3, 4 or 5 independently
selected R.sup.b substituents.
[0317] In some embodiments, R.sup.10 is a spirocyclic C.sub.5-10
membered cycloalkyl or a spirocyclic 5-10 membered
heterocycloalkyl, each of which is optionally substituted with 1,
2, 3, 4 or 5 independently selected R.sup.b substituents.
[0318] In some embodiments, R.sup.10 is a bridged bicyclic
C.sub.5-10 membered cycloalkyl or a bridged bicyclic 6-10 membered
heterocycloalkyl, which is optionally substituted with 1, 2, 3, 4
or 5 independently selected R.sup.b substituents.
[0319] In some embodiments, R.sup.10 is selected from:
##STR00011## ##STR00012## ##STR00013##
[0320] In some embodiments, R.sup.10 is selected from:
##STR00014##
[0321] In some embodiments, R.sup.10 is
##STR00015##
[0322] In some embodiments, L is
##STR00016##
or --SO.sub.2--, wherein each R.sup.11 is independently H or
C.sub.1-6 alkyl optionally substituted with 1 or 2 R.sup.q
substituents and wherein the single wavy line indicates the point
of attachment to R.sup.10 and the double wavy line indicates the
point of attachment to the 6-membered ring A.
[0323] In some embodiments, L is
##STR00017##
or --SO.sub.2--, wherein each R.sup.11 is independently H or
C.sub.1-6 alkyl.
[0324] In some embodiments, L is
##STR00018##
or --SO.sub.2--, wherein each R.sup.11 is H or methyl.
[0325] In some embodiments, L is
##STR00019##
and R.sup.11 is H or C.sub.1-6 alkyl.
[0326] In some embodiments, L is
##STR00020##
and R.sup.11 is H or C.sub.1-6 alkyl.
[0327] In some embodiments, L is --SO.sub.2--.
[0328] In some embodiments, L is
##STR00021##
SO.sub.2 or
##STR00022##
[0330] In some embodiments, L is
##STR00023##
SO.sub.2 or
##STR00024##
[0331] and R.sup.11 is H or C.sub.1-6 alkyl.
[0332] In some embodiments, -L-R.sup.10 forms a group selected
from:
##STR00025##
wherein each R.sup.a2 is independently selected from H, D, halo,
oxo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-4 haloalkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-14 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered heteroaryl)-C.sub.1-4
alkyl-, and (4-14 membered heterocycloalkyl)-C.sub.1-4 alkyl-,
wherein the C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10
membered heteroaryl, 4-14 membered heterocycloalkyl, C.sub.6-10
aryl-C.sub.1-4 alkyl-, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-,
(5-10 membered heteroaryl)-C.sub.1-4 alkyl- and (4-14 membered
heterocycloalkyl)-C.sub.1-4 alkyl- of R.sup.a1 and R.sup.a2 are
each optionally substituted with 1, 2, 3, 4, or 5 independently
selected R.sup.d substituents, and wherein R.sup.10 and R.sup.11
taken together with the nitrogen atom to which they are attached,
form a 4 to 14-membered heterocycloalkyl (indicated by the dashed
ring structure) having 0 to 4 additional heteroatoms as a ring
member, each of which is independently selected from N, O and S,
wherein the 4 to 14-membered heterocycloalkyl formed by R.sup.10,
R.sup.11 and N is optionally substituted with 1, 2, or 3
independently selected R.sup.b substituents.
[0333] In some embodiments, L is
##STR00026##
and R.sup.10 and R.sup.11 are taken together with the nitrogen atom
to which they are attached to form a 4-, 5-, 6-, 7-, 8-, 9-, or
10-membered heterocycloalkyl having 0 to 1 additional heteroatom as
a ring member selected from N, O and S, wherein the 4-, 5-, 6-, 7-,
8-, 9-, or 10-membered heterocycloalkyl formed by R.sup.10,
R.sup.11 and N is optionally substituted with 1, 2 or 3
independently selected R.sup.q substituents.
[0334] In some embodiments, L is
##STR00027##
and R.sup.10 and R.sup.11 are taken together with the nitrogen atom
to which they are attached to form a 8-, 9-, or 10-membered
heterocycloalkyl having 0 to 1 additional heteroatom as a ring
member selected from N, O, and S, wherein the 8-, 9-, or
10-membered heterocycloalkyl formed by R.sup.10, R.sup.11, and N is
optionally substituted with 1, 2 or 3 independently selected
R.sup.q substituents.
[0335] In some embodiments, -L-R.sup.10 forms a group selected
from:
##STR00028##
wherein X.sup.7, X.sup.8, X.sup.9 are each independently selected
from be C, N, O, or S, wherein p, m and n are each independently 0,
1, 2, 3 or 4; and wherein each formed group is optionally
substituted with 0, 1, 2, 3 or 4 independently selected R.sup.b
substituents.
[0336] In some embodiments, X.sup.7, X.sup.8, X.sup.9 are each
independently C, N or O.
[0337] In some embodiments, X.sup.8 and X.sup.9 are C, and X.sup.7
is selected from C, N or O.
[0338] In some embodiments, X.sup.8 and X.sup.9 are C, and X.sup.7
is selected from C or O.
[0339] In some embodiments, p, m, and n are each independently 0, 1
or 2.
[0340] In some embodiments, p, m, and n are each independently 1 or
2.
[0341] In some embodiments, -L-R.sup.10 forms a group selected
from:
##STR00029##
[0342] In some embodiments, one or more R.sup.b groups of a
compound provided herein is each an independently selected R.sup.q
group. In some embodiments, each R.sup.b group of a compound
provided herein is an independently selected R.sup.q group.
[0343] In some embodiments:
[0344] X.sup.1 is N or CR.sup.1;
[0345] X.sup.2 is N or CR.sup.2;
[0346] X.sup.3 is CR.sup.3;
[0347] X.sup.4 is CR.sup.4;
[0348] X.sup.5 is N or CR.sup.5;
[0349] X.sup.6 is CR.sup.6;
[0350] R.sup.1 is H, halo, or 5-10 membered heteroaryl, wherein
said 5-10 membered heteroaryl is optionally substituted by 1, 2, 3,
4, or 5 independently selected R.sup.b substituents;
[0351] R.sup.2 is H;
[0352] R.sup.3 is H;
[0353] R.sup.4 is H, halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, or C.sub.1-6 haloalkyl, wherein said C.sub.1-6
alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are optionally
substituted by 1, 2, 3, 4, or 5 independently selected R.sup.b
substituents;
[0354] R.sup.5 is H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, or C.sub.1-6 haloalkyl, wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are optionally substituted
by 1, 2, 3, 4, or 5 independently selected R.sup.b
substituents;
[0355] R.sup.6 is H, halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, OR.sup.a1, SR.sup.a1,
C(O)R.sup.a1, C(O)NR.sup.a1R.sup.a1, C(O)OR.sup.a1, OC(O)R.sup.a1,
or OC(O)NR.sup.a1R.sup.a1, wherein said C.sub.1-6 alkyl, C.sub.2-6
alkenyl, and C.sub.2-6 alkynyl are optionally substituted by 1, 2,
3, 4, or 5 independently selected R.sup.b substituents;
[0356] R.sup.7 is H, methyl or ethyl, wherein said methyl and ethyl
are each optionally substituted with 1, 2 or 3 groups independently
selected from halo, OH, oxo, CN, C.sub.1-6 alkoxy, and C.sub.1_s
haloalkoxy;
[0357] R.sup.8 is H, halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, C6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-14 membered heteroaryl)-C.sub.1-4
alkyl-, or (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl-,
wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-14 membered
heteroaryl)-C.sub.1-4 alkyl-, and (4-10 membered
heterocycloalkyl)-C.sub.14 alkyl- are each optionally substituted
with 1, 2, 3, 4 or 5 independently selected R.sup.b
substituents;
[0358] R.sup.9 is H;
[0359] R.sup.10 is C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 haloalkyl, C.sub.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-14 membered heteroaryl)-C.sub.1-4
alkyl-, or (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl-,
wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-14 membered
heteroaryl)-C.sub.1-4 alkyl-, and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl- are each optionally substituted
with 1, 2, 3, 4 or 5 independently selected R.sup.b
substituents;
[0360] L is
##STR00030##
or --SO.sub.2--;
[0361] each R.sup.11 is independently H or C.sub.1-6 alkyl;
[0362] or when L is
##STR00031##
R.sup.10 and R.sup.11 optionally taken together with the nitrogen
atom to which they are attached, form a 4 to 14-membered
heterocycloalkyl or a 4 to 14-membered heterocycloalkyl-C.sub.1-4
alkyl-, having 0 to 4 additional heteroatoms as a ring member, each
of which is independently selected from N, O and S, wherein the 4
to 14-membered heterocycloalkyl formed by R.sup.10, R.sup.11 and N
is optionally substituted with 1, 2 or 3 independently selected
R.sup.b substituents;
[0363] each R.sup.a1 is independently selected from H, C.sub.1-6
alkyl, C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-14 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered
heteroaryl)-C.sub.1-4 alkyl-, and (4-14 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, wherein the C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-14 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered heteroaryl)-C.sub.1-4
alkyl- and (4-14 membered heterocycloalkyl)-C.sub.1-4 alkyl- of
R.sup.a are each optionally substituted with 1, 2, 3, 4, or 5
R.sup.d substituents;
[0364] each R.sup.b substituent is independently selected from D,
halo, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy,
CN, OR.sup.c, C(O)R.sup.c, C(O)NR.sup.cR.sup.c,
OC(O)NR.sup.cR.sup.c, NR.sup.cR.sup.c, NR.sup.cC(O)R.sup.c,
NR.sup.cC(O)OR.sup.c, NR.sup.cC(O)NR.sup.cR.sup.c, S(O)R.sup.c,
S(O)NR.sup.cR.sup.c, S(O).sub.2R.sup.c or
S(O).sub.2NR.sup.cR.sup.c; wherein the C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, and C.sub.1-4haloalkoxy of R.sup.a1 are each further
optionally substituted with 1, 2, or 3 independently selected
R.sup.d substituents;
[0365] each R.sup.c is independently selected from H, C.sub.1-6
alkyl, C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl, and C.sub.2-6
alkynyl;
[0366] each R.sup.d is independently selected from C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, and OR.sup.e; and
[0367] each R.sup.e is independently selected from H, C.sub.1-6
alkyl, C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl, and C.sub.2-6
alkynyl.
[0368] In some embodiments:
[0369] X.sup.1 is N or CR.sup.1;
[0370] X.sup.2 is N or CR.sup.2;
[0371] X.sup.3 is CR.sup.3;
[0372] X.sup.4 is CR.sup.4;
[0373] X.sup.5 is N or CR.sup.5;
[0374] X.sup.6 is CR.sup.6;
[0375] R.sup.1 is H, halo, or 5-10 membered heteroaryl, wherein
said 5-10 membered heteroaryl is optionally substituted by 1, 2, 3,
4, or 5 independently selected R.sup.b substituents;
[0376] R.sup.2 is H;
[0377] R.sup.3 is H;
[0378] R.sup.4 is H, halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, or C.sub.1-6 haloalkyl, wherein said C.sub.1-6
alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are optionally
substituted by 1, 2, 3, 4, or 5 independently selected R.sup.b
substituents;
[0379] R.sup.5 is H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, or C.sub.1-6 haloalkyl, wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are optionally substituted
by 1, 2, 3, 4, or 5 independently selected R.sup.b
substituents;
[0380] R.sup.6 is H, halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, OR.sup.a1, SR.sup.a1,
C(O)R.sup.a1, C(O)NR.sup.a1R.sup.a1, C(O)OR.sup.a1, OC(O)R.sup.a1,
or OC(O)NR.sup.a1R.sup.a1, wherein said C.sub.1-6 alkyl, C.sub.2-6
alkenyl, and C.sub.2-6 alkynyl are optionally substituted by 1, 2,
3, 4, or 5 independently selected R.sup.b substituents;
[0381] R.sup.7 is H, methyl or ethyl, wherein said methyl and ethyl
are each optionally substituted with 1, 2 or 3 groups independently
selected from halo, OH, oxo, CN, C.sub.1-6 alkoxy, and C.sub.1-6
haloalkoxy;
[0382] R.sup.8 is H, halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, C.sub.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-14 membered heteroaryl)-C.sub.1-4
alkyl-, or (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl-,
wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-14 membered
heteroaryl)-C.sub.1-4 alkyl-, and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl- are each optionally substituted
with 1, 2, 3, 4 or 5 independently selected R.sup.b
substituents;
[0383] R.sup.9 is H;
[0384] R.sup.10 is C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 haloalkyl, C.sub.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-14 membered heteroaryl)-C.sub.1-4
alkyl-, or (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl-,
wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-14 membered
heteroaryl)-C.sub.1-4 alkyl-, and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl- are each optionally substituted
with 1, 2, 3, 4 or 5 independently selected R.sup.b
substituents;
[0385] L is
##STR00032##
or --SO.sub.2--;
[0386] each R.sup.11 is independently H or C.sub.1-6 alkyl;
[0387] or when L is
##STR00033##
R.sup.10 and R.sup.11 optionally taken together with the nitrogen
atom to which they are attached, form 4-, 5-, 6- or 7-membered
heterocycloalkyl having 0 to 1 additional heteroatom as a ring
member, which is selected from N, O and S, wherein the 4-, 5-, 6-
or 7-membered heterocycloalkyl formed by R.sup.10, R.sup.11 and N
is optionally substituted with 1, 2 or 3 independently selected
R.sup.q substituents;
[0388] each R.sup.a1 is independently selected from H, C.sub.1-6
alkyl, C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered
heteroaryl)-C.sub.1-4 alkyl-, and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, wherein the C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered heteroaryl)-C.sub.1-4
alkyl- and (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl- of
R.sup.a are each optionally substituted with 1, 2, 3, 4, or 5
R.sup.d substituents;
[0389] each R.sup.b substituent is independently selected from
halo, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy,
CN, OR.sup.c, C(O)R.sup.c, C(O)NR.sup.cR.sup.c,
OC(O)NR.sup.cR.sup.c, NR.sup.cR.sup.c, NR.sup.cC(O)R.sup.c,
NR.sup.cC(O)OR.sup.c, NR.sup.cC(O)NR.sup.cR.sup.c, S(O)R.sup.c,
S(O)NR.sup.cR.sup.c, S(O).sub.2R.sup.c or
S(O).sub.2NR.sup.cR.sup.c; wherein the C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, and C.sub.1-4haloalkoxy of R.sup.b are each further
optionally substituted with 1, 2, or 3 independently selected
R.sup.d substituents;
[0390] each R.sup.c is independently selected from H, C.sub.1-6
alkyl, C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl, and C.sub.2-6
alkynyl;
[0391] each R.sup.d is independently selected from C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, and OR.sup.c; and
[0392] each R.sup.e is independently selected from H, C.sub.1-6
alkyl, C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl, and C.sub.2-6
alkynyl.
[0393] In some embodiments:
[0394] X.sup.1 is N or CR.sup.1;
[0395] X.sup.2 is N or CR.sup.2;
[0396] X.sup.3 is CR.sup.3;
[0397] X.sup.4 is CR.sup.4;
[0398] X.sup.5 is N or CR.sup.5;
[0399] X.sup.6 is CR.sup.6;
[0400] R.sup.1 is H, halo, or 5-6 membered heteroaryl, wherein said
5-6 membered heteroaryl is optionally substituted by 1, 2, 3, 4, or
5 independently selected R.sup.b substituents;
[0401] R.sup.2 is H;
[0402] R.sup.3 is H;
[0403] R.sup.4 is H, halo, C.sub.1-6 alkyl, or C.sub.1-6
haloalkyl;
[0404] R.sup.5 is H, C.sub.1-6 alkyl, or C.sub.1-6 haloalkyl;
[0405] R.sup.6 is H, halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
OR.sup.a1, SR.sup.a1, C(O)R.sup.a1, C(O)NR.sup.a1R.sup.a1,
C(O)OR.sup.a1, OC(O)R.sup.a1, or OC(O)NR.sup.a1R.sup.a1, wherein
said C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are
optionally substituted by 1, 2, 3, 4, or 5 independently selected
R.sup.b substituents;
[0406] R.sup.7 is H, methyl or ethyl, wherein said methyl and ethyl
are each optionally substituted with 1, 2 or 3 groups independently
selected from halo, OH, oxo, CN, C.sub.1-6 alkoxy, and C.sub.1-6
haloalkoxy;
[0407] R.sup.8 is H, halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, C.sub.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-14 membered heteroaryl)-C.sub.1-4
alkyl-, or (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl-,
wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-14 membered
heteroaryl)-C.sub.1-4 alkyl-, and (4-10 membered
heterocycloalkyl)-C.sub.14 alkyl- are each optionally substituted
with 1, 2, 3, 4 or 5 independently selected R.sup.b
substituents;
[0408] R.sup.9 is H;
[0409] R.sup.10 is C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 haloalkyl, C.sub.6-10 aryl,
C.sub.3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-14 membered heteroaryl)-C.sub.1-4
alkyl-, or (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl-,
wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-14 membered
heteroaryl)-C.sub.1-4 alkyl-, and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl- are each optionally substituted
with 1, 2, 3, 4 or 5 independently selected R.sup.b
substituents;
[0410] L is
##STR00034##
or --SO.sub.2--;
[0411] each R.sup.11 is independently H or C.sub.1-6 alkyl;
[0412] or when L is
##STR00035##
R.sup.10 and R.sup.11 optionally taken together with the nitrogen
atom to which they are attached, form a 4 to 6-membered
heterocycloalkyl or a 4 to 14-membered heterocycloalkyl-C.sub.14
alkyl-, having 0 to 1 additional heteroatoms as a ring member, each
of which is independently selected from N, O and S, wherein the 4
to 6-membered heterocycloalkyl formed by R.sup.10, R.sup.11 and N
is optionally substituted with 1, 2 or 3 independently selected
R.sup.b substituents;
[0413] each R.sup.a1 is independently selected from H and C.sub.1-6
alkyl;
[0414] each R.sup.b is independently selected from halo, C.sub.1-4
alkyl, C.sub.3-6 cycloalkyl, CN, OR.sup.c, C(O)NR.sup.cR.sup.c,
NR.sup.cR.sup.c, NR.sup.cC(O)OR.sup.c, S(O)R.sup.c, or
S(O).sub.2R.sup.c; wherein the C.sub.1-4 alkyl of R.sup.b is
further optionally substituted with 1, 2, or 3 independently
selected R.sup.d substituents;
[0415] each R.sup.c is independently selected from H, C.sub.1-6
alkyl, C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl, and C.sub.2-6
alkynyl;
[0416] each R.sup.d is independently selected from C.sub.1_s alkyl,
C.sub.1-6 haloalkyl, OR.sup.e; and
[0417] each R.sup.e is independently selected from H, C.sub.1-6
alkyl, C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl, and C.sub.2-6
alkynyl.
[0418] In some embodiments:
[0419] X.sup.1 is N or CR.sup.1;
[0420] X.sup.2 is N or CR.sup.2;
[0421] X.sup.3 is CR.sup.3;
[0422] X.sup.4 is CR.sup.4;
[0423] X.sup.5 is N or CR.sup.5;
[0424] X.sup.6 is CR.sup.6;
[0425] R.sup.1 is H, halo, or 5-6 membered heteroaryl, wherein said
5-6 membered heteroaryl is optionally substituted by 1, 2, 3, 4, or
5 independently selected R.sup.b substituents;
[0426] R.sup.2 is H;
[0427] R.sup.3 is H;
[0428] R.sup.4 is H, halo, C.sub.1-6 alkyl, or C.sub.1-6
haloalkyl;
[0429] R.sup.8 is H, C.sub.1-6 alkyl, or C.sub.1-6 haloalkyl;
[0430] R.sup.6 is H, halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
OR.sup.a1, SR.sup.a1, C(O)R.sup.a1, C(O)NR.sup.a1R.sup.a1,
C(O)OR.sup.a1, OC(O)R.sup.a1, or OC(O)NR.sup.a1R.sup.a1, wherein
said C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are
optionally substituted by 1, 2, 3, 4, or 5 independently selected
R.sup.b substituents;
[0431] R.sup.7 is H, methyl or ethyl, wherein said methyl and ethyl
are each optionally substituted with 1, 2 or 3 groups independently
selected from halo, OH, oxo, CN, C.sub.1-6 alkoxy, and C.sub.1-6
haloalkoxy;
[0432] R.sup.8 is H, halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, C6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-14 membered heteroaryl)-C.sub.1-4
alkyl-, or (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl-,
wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.6-10 aryl, C.sub.3_10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-14 membered
heteroaryl)-C.sub.1-4 alkyl-, and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl- are each optionally substituted
with 1, 2, 3, 4 or 5 independently selected R.sup.b
substituents;
[0433] R.sup.9 is H;
[0434] R.sup.10 is C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 haloalkyl, C.sub.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-14 membered heteroaryl)-C.sub.1-4
alkyl-, or (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl-,
wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-14 membered
heteroaryl)-C.sub.1-4 alkyl-, and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl- are each optionally substituted
with 1, 2, 3, 4 or 5 independently selected R.sup.b substituents; L
is
##STR00036##
or --SO.sub.2--;
[0435] each R.sup.11 is independently H or C.sub.1-6 alkyl;
[0436] or when L is
##STR00037##
R.sup.10 and R.sup.11 optionally taken together with the nitrogen
atom to which they are attached, form 4-, 5- or 6-membered
heterocycloalkyl having 0 to 1 additional heteroatom as a ring
member, which is selected from N, O and S, wherein the 4-, 5- or
6-membered heterocycloalkyl formed by R.sup.10, R.sup.11 and N is
optionally substituted with 1, 2 or 3 independently selected
R.sup.q substituents;
[0437] each R.sup.a1 is independently selected from H and C.sub.1-6
alkyl;
[0438] each R.sup.b is independently selected from halo, C.sub.1-4
alkyl, C.sub.3-6 cycloalkyl, CN, OR.sup.c, C(O)NR.sup.cR.sup.c,
NR.sup.cR.sup.c, NR.sup.cC(O)OR.sup.c, S(O)R.sup.c, or
S(O).sub.2R.sup.c; wherein the C.sub.1-4 alkyl of R.sup.b is
further optionally substituted with 1, 2, or 3 independently
selected R.sup.d substituents;
[0439] each R.sup.c is independently selected from H, C.sub.1-6
alkyl, C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl, and C.sub.2-6
alkynyl;
[0440] each R.sup.d is independently selected from C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, OR.sup.e; and
[0441] each R.sup.e is independently selected from H, C.sub.1-6
alkyl, C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl, and C.sub.2-6
alkynyl.
[0442] In some embodiments:
[0443] X.sup.1 is N or CR.sup.1;
[0444] X.sup.2 is N or CR.sup.2;
[0445] X.sup.3 is CR.sup.3;
[0446] X.sup.4 is CR.sup.4;
[0447] X.sup.5 is N or CR.sup.5;
[0448] X.sup.6 is CR.sup.6;
[0449] R.sup.1 is H, halo, or 5-6 membered heteroaryl, wherein said
5-6 membered heteroaryl is optionally substituted by 1 or 2
independently selected C.sub.1-4 alkyl groups;
[0450] R.sup.2 is H;
[0451] R.sup.3 is H;
[0452] R.sup.4 is H, halo, or C.sub.1-6 alkyl;
[0453] R.sup.5 is H or C.sub.1-6 alkyl;
[0454] R.sup.6 is H, halo, C.sub.1-6 alkyl, or OR.sup.a1;
[0455] R.sup.7 is H, methyl or ethyl, wherein said methyl and ethyl
are each optionally substituted with 1, 2 or 3 groups independently
selected from halo, OH, oxo, CN, C.sub.1-6 alkoxy, and C.sub.1-6
haloalkoxy;
[0456] R.sup.8 is halo, C.sub.1-6 alkyl, phenyl, or 5-6 membered
heteroaryl, wherein C.sub.1-6 alkyl, C.sub.6-10 aryl and 5-6
membered heteroaryl are each optionally substituted with 1, 2 or 3
independently selected R.sup.b substituents;
[0457] R.sup.9 is H;
[0458] R.sup.10 is C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, 4-6
membered heterocycloalkyl, or (4-6 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, wherein the C.sub.1-6 alkyl,
phenyl, C.sub.3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and
(4-6 membered heterocycloalkyl)-C.sub.1-4 alkyl- are each
optionally substituted with 1, 2, 3, 4 or 5 independently selected
R.sup.b substituents;
[0459] L is
##STR00038##
SO.sub.2 or
##STR00039##
[0461] R.sup.11 is H or C.sub.1-6 alkyl;
[0462] or when L is
##STR00040##
R.sup.10 and R.sup.11 optionally taken together with the nitrogen
atom to which they are attached, form a 4 to 6-membered
heterocycloalkyl or a 4 to 14-membered heterocycloalkyl-C.sub.14
alkyl-, having 0 to 1 additional heteroatoms as a ring member, each
of which is independently selected from N, O and S, wherein the 4
to 6-membered heterocycloalkyl formed by R.sup.10, R.sup.11 and N
is optionally substituted with 1, 2 or 3 independently selected R
substituents;
[0463] each R.sup.a1 is H or C.sub.1-6 alkyl;
[0464] each R.sup.b substituent is independently selected from
halo, C.sub.1-4 alkyl, CN, OR.sup.c, C(O)NR.sup.cR.sup.c,
NR.sup.cR.sup.c, NR.sup.cC(O)OR.sup.c, S(O)R.sup.c, or
S(O).sub.2R.sup.c; wherein the C.sub.1-4 alkyl of R.sup.b is
further optionally substituted with 1, 2, or 3 independently
selected R.sup.d substituents;
[0465] each R.sup.c is independently selected from H and C.sub.1-6
alkyl;
[0466] each R.sup.d is independently selected from C.sub.1-6 alkyl
and OR.sup.e; and
[0467] each R.sup.e is independently selected from H and C.sub.1-6
alkyl.
[0468] In some embodiments:
[0469] X.sup.1 is N or CR.sup.1;
[0470] X.sup.2 is N or CR.sup.2;
[0471] X.sup.3 is CR.sup.3;
[0472] X.sup.4 is CR.sup.4;
[0473] X.sup.5 is N or CR.sup.5;
[0474] X.sup.6 is CR.sup.6;
[0475] R.sup.1 is H, halo, or 5-6 membered heteroaryl, wherein said
5-6 membered heteroaryl is optionally substituted by 1 or 2
independently selected C.sub.1-4 alkyl groups;
[0476] R.sup.2 is H;
[0477] R.sup.3 is H;
[0478] R.sup.4 is H, halo, or C.sub.1-6 alkyl;
[0479] R.sup.5 is H or C.sub.1-6 alkyl;
[0480] R.sup.6 is H, halo, C.sub.1-6 alkyl, or OR.sup.a1;
[0481] R.sup.7 is H, methyl or ethyl, wherein said methyl and ethyl
are each optionally substituted with 1, 2 or 3 groups independently
selected from halo, OH, oxo, CN, C.sub.1-6 alkoxy, and C.sub.1-6
haloalkoxy;
[0482] R.sup.8 is halo, C.sub.1-6 alkyl, phenyl, or 5-6 membered
heteroaryl, wherein C.sub.1-6 alkyl, C.sub.6-10 aryl and 5-6
membered heteroaryl are each optionally substituted with 1, 2 or 3
independently selected R substituents;
[0483] R.sup.9 is H;
[0484] R.sup.10 is C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, 4-6
membered heterocycloalkyl, or (4-6 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, wherein the C.sub.1-6 alkyl,
phenyl, C.sub.3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and
(4-6 membered heterocycloalkyl)-C.sub.1-4 alkyl- are each
optionally substituted with 1, 2, 3, 4 or 5 independently selected
R.sup.b substituents;
[0485] L is
##STR00041##
SO.sub.2 or
##STR00042##
[0487] R.sup.11 is H or C.sub.1-6 alkyl;
[0488] or when L is
##STR00043##
R.sup.10 and R.sup.11 optionally taken together with the nitrogen
atom to which they are attached, form a 4-, 5- or 6-membered
heterocycloalkyl having 0 to 1 additional heteroatom as a ring
member, which is selected from N, O and S, wherein the 4-, 5- or
6-membered heterocycloalkyl formed by R.sup.10, R.sup.11 and N is
optionally substituted with 1, 2 or 3 independently selected
R.sup.q substituents;
[0489] each R.sup.a1 is H or C.sub.1-6 alkyl;
[0490] each R.sup.b substituent is independently selected from
halo, C.sub.1-4 alkyl, CN, OR.sup.c, C(O)NR.sup.cR.sup.c,
NR.sup.cR.sup.c, NR.sup.cC(O)OR.sup.c, S(O)R.sup.c, or
S(O).sub.2R.sup.c; wherein the C.sub.1-4 alkyl of R.sup.b is
further optionally substituted with 1, 2, or 3 independently
selected R.sup.d substituents;
[0491] each R.sup.c is independently selected from H and C.sub.1-6
alkyl;
[0492] each R.sup.d is independently selected from C.sub.1-6 alkyl
and OR.sup.c; and
[0493] each R.sup.e is independently selected from H and C.sub.1-6
alkyl.
[0494] In some embodiments:
[0495] X.sup.1 is N or CR.sup.1;
[0496] X.sup.2 is N or CR.sup.2;
[0497] X.sup.3 is CR.sup.3;
[0498] X.sup.4 is CR.sup.4;
[0499] X.sup.5 is N or CR.sup.5;
[0500] X.sup.6 is CR.sup.6;
[0501] R.sup.1 is H, halo, or pyrazolyl, wherein said pyrazolyl is
optionally substituted by 1 or 2 independently selected C.sub.1-4
alkyl groups;
[0502] R.sup.2 is H;
[0503] R.sup.3 is H;
[0504] R.sup.4 is H, F, CD.sub.3, or methyl;
[0505] R.sup.5 is H or methyl;
[0506] R.sup.6 is H, F, Cl, methyl, methoxy, or ethoxy;
[0507] R.sup.7 is H, methyl, or --C(O)-methyl;
[0508] R.sup.8 is H, Br, Cl, C.sub.1-4 alkyl, phenyl,
1H-pyrazol-5-yl, pyrazol-4-yl, thiazol-5-yl, pyridyl, thiophenyl or
pyrimidinyl, wherein the phenyl, 1H-pyrazol-5-yl, 1H-pyrazol-4-yl,
thiazol-5-yl, pyridyl, thiophenyl and pyrimidinyl are each
optionally substituted with 1 or 2 independently selected R.sup.b
substituents;
[0509] R.sup.9 is H;
[0510] R.sup.10 is methyl, ethyl, propyl, cyclopropyl, cyclobutyl,
cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, or
--CH.sub.2-oxetanyl, each of which is optionally substituted with 1
or 2 independently selected R.sup.b substituents;
[0511] L is
##STR00044##
SO.sub.2 or
##STR00045##
[0513] R.sup.11 is H or methyl;
[0514] or when L is
##STR00046##
R.sup.10 and R.sup.11 optionally taken together with the nitrogen
atom to which they are attached, form 4-, 5- or 6-membered
heterocycloalkyl having 0 to 1 additional heteroatom as a ring
member, which is selected from N, O and S, wherein the 4-, 5- or
6-membered heterocycloalkyl formed by R.sup.10, R.sup.11 and N is
optionally substituted with 1, 2 or 3 independently selected
R.sup.q substituents;
[0515] each R.sup.a1 is H or C.sub.1-6 alkyl;
[0516] each R.sup.b substituent is independently selected from
halo, C.sub.1-4 alkyl, CN, OR.sup.c, C(O)NR.sup.cR.sup.c,
NR.sup.cR.sup.c, NR.sup.cC(O)OR.sup.c, or S(O).sub.2R.sup.c;
wherein the C.sub.1-4 alkyl of R.sup.b is further optionally
substituted with 1, 2, or 3 independently selected R.sup.d
substituents;
[0517] each R.sup.c is independently selected from H and C.sub.1-6
alkyl;
[0518] each R.sup.d is independently OR.sup.e; and
[0519] each R.sup.e is independently selected from H and C.sub.1-6
alkyl.
[0520] In some embodiments:
[0521] X.sup.1 is N or CR.sup.1;
[0522] X.sup.2 is N or CR.sup.2;
[0523] X.sup.3 is CR.sup.3;
[0524] X.sup.4 is CR.sup.4;
[0525] X.sup.5 is N or CR.sup.5;
[0526] X.sup.6 is CR.sup.6;
[0527] R.sup.1 is H, halo, or pyrazolyl, wherein said pyrazolyl is
optionally substituted by 1 or 2 independently selected C.sub.1-4
alkyl groups;
[0528] R.sup.2 is H;
[0529] R.sup.3 is H;
[0530] R.sup.4 is H, F, or methyl;
[0531] R.sup.5 is H or methyl;
[0532] R.sup.6 is H, F, Cl, methyl, methoxy, or ethoxy;
[0533] R.sup.7 is H, methyl, or --C(O)-methyl;
[0534] R.sup.8 is H, Br, Cl, C.sub.1-4 alkyl, phenyl,
1H-pyrazol-5-yl, pyrazol-4-yl, thiazol-5-yl, pyridyl, thiophenyl or
pyrimidinyl, wherein the phenyl, 1H-pyrazol-5-yl, 1H-pyrazol-4-yl,
thiazol-5-yl, pyridyl, thiophenyl and pyrimidinyl are each
optionally substituted with 1 or 2 independently selected R.sup.b
substituents;
[0535] R.sup.9 is H;
[0536] R.sup.10 is methyl, ethyl, propyl, cyclopropyl, cyclobutyl,
cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, or
--CH.sub.2-oxetanyl, each of which is optionally substituted with 1
or 2 independently selected R.sup.b substituents;
[0537] L is
##STR00047##
SO.sub.2 or
##STR00048##
[0539] R.sup.11 is H or methyl;
[0540] or when L is
##STR00049##
R.sup.10 and R.sup.11 optionally taken together with the nitrogen
atom to which they are attached, form 4-, 5- or 6-membered
heterocycloalkyl having 0 to 1 additional heteroatom as a ring
member, which is selected from N, O and S, wherein the 4-, 5- or
6-membered heterocycloalkyl formed by R.sup.10, R.sup.11 and N is
optionally substituted with 1, 2 or 3 independently selected
R.sup.q substituents;
[0541] each R.sup.a1 is H or C.sub.1-6 alkyl;
[0542] each R.sup.b substituent is independently selected from
halo, C.sub.1-4 alkyl, CN, OR.sup.c, C(O)NR.sup.cR.sup.c,
NR.sup.cR.sup.c, NR.sup.cC(O)OR.sup.c, or S(O).sub.2R.sup.c;
wherein the C.sub.1-4 alkyl of R.sup.b is further optionally
substituted with 1, 2, or 3 independently selected R.sup.d
substituents;
[0543] each R.sup.c is independently selected from H and C.sub.1-6
alkyl;
[0544] each R.sup.d is independently OR.sup.e; and
[0545] each R.sup.e is independently selected from H and C.sub.1-6
alkyl.
[0546] In some embodiments:
[0547] X.sup.1 is N or CR.sup.1;
[0548] X.sup.2 is N or CR.sup.2;
[0549] X.sup.3 is CR.sup.3;
[0550] X.sup.4 is CR.sup.4;
[0551] X.sup.5 is N or CR.sup.5;
[0552] X.sup.6 is CR.sup.6;
[0553] R.sup.1 is H, halo, or 5-10 membered heteroaryl, wherein
said 5-10 membered heteroaryl is optionally substituted by 1, 2, 3,
4, or 5 independently selected R.sup.b substituents;
[0554] R.sup.2 is H;
[0555] R.sup.3 is H;
[0556] R.sup.4 is H, halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, or C.sub.1-6 haloalkyl, wherein said C.sub.1-6
alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are optionally
substituted by 1, 2, 3, 4, or 5 independently selected R.sup.b
substituents;
[0557] R.sup.5 is H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, or C.sub.1-6 haloalkyl, wherein said C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are optionally substituted
by 1, 2, 3, 4, or 5 independently selected R.sup.b
substituents;
[0558] R.sup.6 is H, halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, OR.sup.a1, SR.sup.a1,
C(O)R.sup.a1, C(O)NR.sup.a1R.sup.a1, C(O)OR.sup.a1, OC(O)R.sup.a1,
or OC(O)NR.sup.a1R.sup.a1, wherein said C.sub.1-6 alkyl, C.sub.2-6
alkenyl, and C.sub.2-6 alkynyl are optionally substituted by 1, 2,
3, 4, or 5 independently selected R.sup.b substituents;
[0559] R.sup.7 is H, methyl or ethyl, wherein said methyl and ethyl
are each optionally substituted with 1, 2 or 3 groups independently
selected from halo, OH, oxo, CN, C.sub.1-6 alkoxy, and C.sub.1-6
haloalkoxy;
[0560] R.sup.8 is H, halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, C.sub.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-14 membered heteroaryl)-C.sub.1-4
alkyl-, or (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl-,
wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-14 membered
heteroaryl)-C.sub.1-4 alkyl-, and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl- are each optionally substituted
with 1, 2, 3, 4 or 5 independently selected R.sup.b
substituents;
[0561] R.sup.9 is H;
[0562] R.sup.10 is C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 haloalkyl, C.sub.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-14 membered heteroaryl)-C.sub.1-4
alkyl-, or (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl-,
wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-14 membered
heteroaryl)-C.sub.1-4 alkyl-, and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl- are each optionally substituted
with 1, 2, 3, 4 or 5 independently selected R.sup.b
substituents;
[0563] L is
##STR00050##
or --SO.sub.2--;
[0564] each R.sup.11 is independently H or C.sub.1-6 alkyl;
[0565] each R.sup.a1 is independently selected from H, C.sub.1-6
alkyl, C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered
heteroaryl)-C.sub.1-4 alkyl-, and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, wherein the C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl,
C.sub.3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-10 membered heteroaryl)-C.sub.1-4
alkyl- and (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl- of
R.sup.a are each optionally substituted with 1, 2, 3, 4, or 5
R.sup.d substituents;
[0566] each R.sup.b substituent is independently selected from
halo, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy,
CN, OR.sup.c, C(O)R.sup.c, C(O)NR.sup.cR.sup.c,
OC(O)NR.sup.cR.sup.c, NR.sup.cR.sup.c, NR.sup.cC(O)R.sup.c,
NR.sup.cC(O)OR.sup.c, NR.sup.cC(O)NR.sup.cR.sup.c, S(O)R.sup.c,
S(O)NR.sup.cR.sup.c, S(O).sub.2R.sup.c or
S(O).sub.2NR.sup.cR.sup.c; wherein the C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, and C.sub.1-4haloalkoxy of R.sup.b are each further
optionally substituted with 1, 2, or 3 independently selected
R.sup.d substituents;
[0567] each R.sup.c is independently selected from H, C.sub.1-6
alkyl, C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl, and C.sub.2-6
alkynyl;
[0568] each R.sup.d is independently selected from C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, and OR.sup.c; and
[0569] each R.sup.e is independently selected from H, C.sub.1-6
alkyl, C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl, and C.sub.2-6
alkynyl.
[0570] In some embodiments:
[0571] X.sup.1 is N or CR.sup.1;
[0572] X.sup.2 is N or CR.sup.2;
[0573] X.sup.3 is CR.sup.3;
[0574] X.sup.4 is CR.sup.4;
[0575] X.sup.5 is N or CR.sup.5;
[0576] X.sup.6 is CR.sup.6;
[0577] R.sup.1 is H, halo, or 5-6 membered heteroaryl, wherein said
5-6 membered heteroaryl is optionally substituted by 1, 2, 3, 4, or
5 independently selected R.sup.b substituents;
[0578] R.sup.2 is H;
[0579] R.sup.3 is H;
[0580] R.sup.4 is H, halo, C.sub.1-6 alkyl, or C.sub.1-6
haloalkyl;
[0581] R.sup.5 is H, C.sub.1-6 alkyl, or C.sub.1-6 haloalkyl;
[0582] R.sup.6 is H, halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
OR.sup.a1, SR.sup.a1, C(O)R.sup.a1, C(O)NR.sup.a1R.sup.a1,
C(O)OR.sup.a1, OC(O)R.sup.a1, or OC(O)NR.sup.a1R.sup.a1, wherein
said C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl are
optionally substituted by 1, 2, 3, 4, or 5 independently selected
R.sup.b substituents;
[0583] R.sup.7 is H, methyl or ethyl, wherein said methyl and ethyl
are each optionally substituted with 1, 2 or 3 groups independently
selected from halo, OH, oxo, CN, C.sub.1-6 alkoxy, and C.sub.1-6
haloalkoxy;
[0584] R.sup.8 is H, halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, C.sub.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-14 membered heteroaryl)-C.sub.1-4
alkyl-, or (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl-,
wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-14 membered
heteroaryl)-C.sub.1-4 alkyl-, and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl- are each optionally substituted
with 1, 2, 3, 4 or 5 independently selected R.sup.b
substituents;
[0585] R.sup.9 is H;
[0586] R.sup.10 is C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 haloalkyl, C.sub.6-10 aryl, C.sub.3-10
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-, C.sub.3-10
cycloalkyl-C.sub.1-4 alkyl-, (5-14 membered heteroaryl)-C.sub.1-4
alkyl-, or (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl-,
wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.6-10 aryl, C.sub.3-10 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered heterocycloalkyl, C.sub.6-10 aryl-C.sub.1-4 alkyl-,
C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl-, (5-14 membered
heteroaryl)-C.sub.1-4 alkyl-, and (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl- are each optionally substituted
with 1, 2, 3, 4 or 5 independently selected R.sup.b
substituents;
[0587] Li is
##STR00051##
or --SO.sub.2--;
[0588] each R.sup.11 is independently H or C.sub.1-6 alkyl;
[0589] each R.sup.a1 is independently selected from H and C.sub.1-6
alkyl;
[0590] each R.sup.b is independently selected from halo, C.sub.1-4
alkyl, CN, OR.sup.c, C(O)NR.sup.cR.sup.c, NR.sup.cR.sup.c,
NR.sup.cC(O)OR.sup.c, S(O)R.sup.c, or S(O).sub.2R.sup.c; wherein
the C.sub.1-4 alkyl of R.sup.b is further optionally substituted
with 1, 2, or 3 independently selected R.sup.d substituents;
[0591] each R.sup.c is independently selected from H, C.sub.1-6
alkyl, C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl, and C.sub.2-6
alkynyl;
[0592] each R.sup.d is independently selected from C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, OR.sup.e; and
[0593] each R.sup.e is independently selected from H, C.sub.1-6
alkyl, C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl, and C.sub.2-6
alkynyl.
[0594] In some embodiments:
[0595] X.sup.1 is N or CR.sup.1;
[0596] X.sup.2 is N or CR.sup.2;
[0597] X.sup.3 is CR.sup.3;
[0598] X.sup.4 is CR.sup.4;
[0599] X.sup.5 is N or CR.sup.5;
[0600] X.sup.6 is CR.sup.6;
[0601] R.sup.1 is H, halo, or 5-6 membered heteroaryl, wherein said
5-6 membered heteroaryl is optionally substituted by 1 or 2
independently selected C.sub.1-4 alkyl groups;
[0602] R.sup.2 is H;
[0603] R.sup.3 is H;
[0604] R.sup.4 is H, halo, or C.sub.1-6 alkyl;
[0605] R.sup.5 is H or C.sub.1-6 alkyl;
[0606] R.sup.6 is H, halo, C.sub.1-6 alkyl, or OR.sup.a1;
[0607] R.sup.7 is H, methyl or ethyl, wherein said methyl and ethyl
are each optionally substituted with 1, 2 or 3 groups independently
selected from halo, OH, oxo, CN, C.sub.1-6 alkoxy, and C.sub.1-6
haloalkoxy;
[0608] R.sup.8 is halo, C.sub.1-6 alkyl, phenyl, or 5-6 membered
heteroaryl, wherein C.sub.1-6 alkyl, C.sub.6-10 aryl and 5-6
membered heteroaryl are each optionally substituted with 1, 2 or 3
independently selected R substituents;
[0609] R.sup.9 is H;
[0610] R.sup.10 is C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, 4-6
membered heterocycloalkyl, or (4-6 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, wherein the C.sub.1-6 alkyl,
phenyl, C.sub.3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and
(4-6 membered heterocycloalkyl)-C.sub.1-4 alkyl- are each
optionally substituted with 1, 2, 3, 4 or 5 independently selected
R.sup.b substituents;
[0611] L is
##STR00052##
SO.sub.2 or
##STR00053##
[0613] R.sup.11 is H or C.sub.1-6 alkyl;
[0614] each R.sup.a1 is independently H or C.sub.1-6 alkyl;
[0615] each R.sup.b substituent is independently selected from
halo, C.sub.1-4 alkyl, CN, OR.sup.c, C(O)NR.sup.cR.sup.c,
NR.sup.cR.sup.c, NR.sup.cC(O)OR.sup.c, S(O)R.sup.c, or
S(O).sub.2R.sup.c; wherein the C.sub.1-4 alkyl of R.sup.b is
further optionally substituted with 1, 2, or 3 independently
selected R.sup.d substituents;
[0616] each R.sup.c is independently selected from H and C.sub.1-6
alkyl;
[0617] each R.sup.d is independently selected from C.sub.1-6 alkyl
and OR.sup.c; and
[0618] each R.sup.e is independently selected from H and C.sub.1-6
alkyl.
[0619] In some embodiments:
[0620] X.sup.1 is N or CR.sup.1;
[0621] X.sup.2 is N or CR.sup.2;
[0622] X.sup.3 is CR.sup.3;
[0623] X.sup.4 is CR.sup.4;
[0624] X.sup.5 is N or CR.sup.5;
[0625] X.sup.6 is CR.sup.6;
[0626] R.sup.1 is H, halo, or pyrazolyl, wherein said pyrazolyl is
optionally substituted by 1 or 2 independently selected C.sub.1-4
alkyl groups;
[0627] R.sup.2 is H;
[0628] R.sup.3 is H;
[0629] R.sup.4 is H, F, or methyl;
[0630] R.sup.5 is H or methyl;
[0631] R.sup.6 is H, F, Cl, methyl, methoxy, or ethoxy;
[0632] R.sup.7 is H, methyl, or --C(O)-methyl;
[0633] R.sup.8 is H, Br, Cl, C.sub.1-4 alkyl, phenyl,
1H-pyrazol-5-yl, pyrazol-4-yl, thiazol-5-yl, pyridyl, thiophenyl or
pyrimidinyl, wherein the phenyl, 1H-pyrazol-5-yl, 1H-pyrazol-4-yl,
thiazol-5-yl, pyridyl, thiophenyl and pyrimidinyl are each
optionally substituted with 1 or 2 independently selected R.sup.b
substituents;
[0634] R.sup.9 is H;
[0635] R.sup.10 is methyl, ethyl, propyl, cyclopropyl, cyclobutyl,
cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, or
--CH.sub.2-oxetanyl, each of which is optionally substituted with 1
or 2 independently selected R.sup.b substituents;
[0636] L is
##STR00054##
SO.sub.2 or
##STR00055##
[0638] R.sup.11 is H or methyl;
[0639] each R.sup.a1 is independently H or C.sub.1-6 alkyl;
[0640] each R.sup.b substituent is independently selected from
halo, C.sub.1-4 alkyl, CN, OR.sup.c, C(O)NR.sup.cR.sup.c,
NR.sup.cR.sup.c, NR.sup.cC(O)OR.sup.c, or S(O).sub.2R.sup.c;
wherein the C.sub.1-4 alkyl of R.sup.b is further optionally
substituted with 1, 2, or 3 independently selected R.sup.d
substituents;
[0641] each R.sup.c is independently selected from H and C.sub.1-6
alkyl;
[0642] each R.sup.d is independently OR.sup.e; and
[0643] each R.sup.e is independently selected from H and C.sub.1-6
alkyl.
[0644] In the last four embodiments, L is preferably
##STR00056##
wherein R.sup.11 is H or methyl.
[0645] In some embodiments:
[0646] X.sup.1 is N;
[0647] X.sup.2 is N;
[0648] X.sup.3 is CH;
[0649] X.sup.4 is CR.sup.4;
[0650] X.sup.5 is CH;
[0651] X.sup.6 is CH;
[0652] R.sup.4 is H, D, F, or C.sub.1-6 alkyl, wherein one or more
hydrogen atoms of the C.sub.1-6 alkyl group are replaced with
deuterium atoms;
[0653] R.sup.7 is H;
[0654] R.sup.8 is H, Br, Cl, C.sub.1-4 alkyl, phenyl,
1H-pyrazol-5-yl, pyrazol-4-yl, thiazol-5-yl, pyridyl, thiophenyl or
pyrimidinyl, wherein the phenyl, 1H-pyrazol-5-yl, 1H-pyrazol-4-yl,
thiazol-5-yl, pyridyl, thiophenyl and pyrimidinyl are each
optionally substituted with 1 or 2 independently selected R.sup.b
substituents;
[0655] R.sup.9 is H;
[0656] R.sup.10 is 4-10 membered heterocycloalkyl or (4-10 membered
heterocycloalkyl)-C.sub.1-4 alkyl-, each of which may be optionally
substituted with 1 or 2 independently selected R.sup.b
substituents;
[0657] L is
##STR00057##
SO.sub.2 or
##STR00058##
[0659] R.sup.11 is H or C.sub.1-6 alkyl;
[0660] each R.sup.b substituent is independently selected from
halo, C.sub.1-4 alkyl, CN, OR.sup.c, C(O)NR.sup.cR.sup.c,
NR.sup.cR.sup.c, NR.sup.cC(O)OR.sup.c, and S(O).sub.2R.sup.c;
wherein the C.sub.1-4 alkyl of R.sup.b is further optionally
substituted with 1, 2, or 3 independently selected R.sup.d
substituents;
[0661] each R.sup.c is independently selected from H and C.sub.1-6
alkyl;
[0662] each R.sup.d is independently OR.sup.e; and
[0663] each R.sup.e is independently selected from H and C.sub.1-6
alkyl.
[0664] In some embodiments:
[0665] X.sup.1 is N;
[0666] X.sup.2 is N;
[0667] X.sup.3 is CH;
[0668] X.sup.4 is CR.sup.4;
[0669] X.sup.5 is CH;
[0670] X.sup.6 is CH;
[0671] R.sup.4 is H, D, F, or C.sub.1-6 alkyl, wherein one or more
hydrogen atoms of the C.sub.1-6 alkyl group are replaced with
deuterium atoms;
[0672] R.sup.7 is H;
[0673] R.sup.8 is H, Br, Cl, C.sub.1-4 alkyl, phenyl,
1H-pyrazol-5-yl, pyrazol-4-yl, thiazol-5-yl, pyridyl, thiophenyl or
pyrimidinyl, wherein the phenyl, 1H-pyrazol-5-yl, 1H-pyrazol-4-yl,
thiazol-5-yl, pyridyl, thiophenyl and pyrimidinyl are each
optionally substituted with 1 or 2 independently selected R.sup.b
substituents;
[0674] R.sup.9 is H;
[0675] R.sup.10 is a bicyclic 6-10 membered heterocycloalkyl, which
is optionally substituted with 1 or 2 independently selected
R.sup.b substituents;
[0676] L is
##STR00059##
SO.sub.2 or
##STR00060##
[0678] R.sup.11 is H or C.sub.1-6 alkyl;
[0679] each R.sup.b substituent is independently selected from
halo, C.sub.1-4 alkyl, CN, OR.sup.c, C(O)NR.sup.cR.sup.c,
NR.sup.cR.sup.c, NR.sup.cC(O)OR.sup.c, and S(O).sub.2R.sup.c;
wherein the C.sub.1-4 alkyl of R.sup.b is further optionally
substituted with 1, 2, or 3 independently selected R.sup.d
substituents;
[0680] each R.sup.c is independently selected from H and C.sub.1-6
alkyl;
[0681] each R.sup.d is independently OR.sup.e; and
[0682] each R.sup.e is independently selected from H and C.sub.1-6
alkyl.
[0683] In some embodiments:
[0684] X.sup.1 is N;
[0685] X.sup.2 is N;
[0686] X.sup.3 is CH;
[0687] X.sup.4 is CR.sup.4;
[0688] X.sup.5 is CH;
[0689] X.sup.6 is CH;
[0690] R.sup.4 is H, D, F, or C.sub.1-6 alkyl, wherein one or more
hydrogen atoms of the C.sub.1-6 alkyl group are replaced with
deuterium atoms;
[0691] R.sup.7 is H;
[0692] R.sup.8 is H, Br, Cl, C.sub.1-4 alkyl, phenyl,
1H-pyrazol-5-yl, pyrazol-4-yl, thiazol-5-yl, pyridyl, thiophenyl or
pyrimidinyl, wherein the phenyl, 1H-pyrazol-5-yl, 1H-pyrazol-4-yl,
thiazol-5-yl, pyridyl, thiophenyl and pyrimidinyl are each
optionally substituted with 1 or 2 independently selected R.sup.b
substituents;
[0693] R.sup.9 is H;
[0694] R.sup.10 is a bicyclic 6-10 membered heterocycloalkyl, which
is optionally substituted with 1 or 2 independently selected
R.sup.b substituents;
[0695] L is
##STR00061##
SO.sub.2 or
##STR00062##
[0697] R.sup.11 is H or C.sub.1-6 alkyl;
[0698] each R.sup.b substituent is independently selected from
halo, C.sub.1-4 alkyl, CN, OR.sup.c, C(O)NR.sup.cR.sup.c,
NR.sup.cR.sup.c, NR.sup.cC(O)OR.sup.c, and S(O).sub.2R; and
[0699] each R.sup.e is independently selected from H and C.sub.1-6
alkyl.
[0700] In some embodiments:
[0701] X.sup.1 is N;
[0702] X.sup.2 is N;
[0703] X.sup.3 is CH;
[0704] X.sup.4 is CR.sup.4;
[0705] X.sup.5 is CH;
[0706] X.sup.6 is CH;
[0707] R.sup.4 is H, D, F, or C.sub.1-6 alkyl, wherein one or more
hydrogen atoms of the C.sub.1-6 alkyl group are replaced with
deuterium atoms;
[0708] R.sup.7 is H;
[0709] R.sup.8 is H, Br, Cl, C.sub.1-4 alkyl, phenyl,
1H-pyrazol-5-yl, pyrazol-4-yl, thiazol-5-yl, pyridyl, thiophenyl or
pyrimidinyl, wherein the phenyl, 1H-pyrazol-5-yl, 1H-pyrazol-4-yl,
thiazol-5-yl, pyridyl, thiophenyl and pyrimidinyl are each
optionally substituted with 1 or 2 independently selected R.sup.b
substituents;
[0710] R.sup.9 is H;
[0711] R.sup.10 is a bicyclic 6-10 membered heterocycloalkyl, which
is optionally substituted with 1 or 2 independently selected
R.sup.b substituents;
[0712] L is
##STR00063##
SO.sub.2 or
##STR00064##
[0714] R.sup.11 is H or C.sub.1-6 alkyl;
[0715] each R.sup.b substituent is independently selected from
halo, C.sub.1-4 alkyl, CN, OR.sup.c, C(O)NR.sup.cR.sup.c,
NR.sup.cR.sup.c, NR.sup.cC(O)OR.sup.c, and S(O).sub.2R.sup.c;
and
[0716] each R.sup.c is independently selected from H and C.sub.1-6
alkyl;
[0717] In some embodiments, L is preferably
##STR00065##
wherein R.sup.11 is H or methyl.
[0718] In some embodiments, the compound is a compound of Formula
(II):
##STR00066##
or a pharmaceutically acceptable salt thereof.
[0719] In some embodiments, the compound is a compound of Formula
(III):
##STR00067##
or a pharmaceutically acceptable salt thereof.
[0720] In some embodiments, the compound is a compound of Formula
(IV):
##STR00068##
or a pharmaceutically acceptable salt thereof.
[0721] In some embodiments, the compound is a compound of Formula
(V):
##STR00069##
or a pharmaceutically acceptable salt thereof.
[0722] In some embodiments, the compound is a compound of Formula
(IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIIa), (IIIb), (IIIc),
(IIId), (IIIe), (IIIf), (IVa), (IVb), (IVc), (IVd), (IVe), (Va),
(Vb), (Vc), (Vd), or (Ve):
##STR00070## ##STR00071## ##STR00072## ##STR00073##
##STR00074##
or a pharmaceutically acceptable salt thereof.
[0723] In the each of the subformulas (II), (III), (IV), (V),
(IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIIa), (IIIb), (IIIc),
(IIId), (IIIe), (IIIf), (IVa), (IVb), (IVc), (IVd), (IVe), (Va),
(Vb), (Vc), (Vd), or (Ve), L is preferably
##STR00075##
wherein R.sup.11 is H or methyl.
[0724] In some embodiments, the compound is a compound of Formula
IIg, IIh, IVg, or IVh:
##STR00076##
or a pharmaceutically acceptable salt or a tautomer thereof.
[0725] In some embodiments of Formulas (IIg), (IIh), (IVg), and
(IVh), L is
##STR00077##
wherein R.sup.11 is H or methyl.
[0726] In some embodiments of Formulas (IIg), (IIh), (IVg), and
(IVh), R.sup.4 is H, D, F, or C.sub.1-6 alkyl, wherein one or more
hydrogen atoms of the C.sub.1-6 alkyl group are replaced with
deuterium atoms.
[0727] In some embodiments of Formulas (IIg), (IIh), (IVg), and
(IVh), R.sup.4 is H, D, F, CD.sub.3, or CH.sub.3.
[0728] In some embodiments, the compound is a compound of Formula
(VI):
##STR00078##
or a pharmaceutically acceptable salt or a tautomer thereof.
[0729] In some embodiments, the compound is a compound of Formula
(VII):
##STR00079##
or a pharmaceutically acceptable salt or a tautomer thereof.
[0730] In some embodiments, the compound is a compound of Formula
(VII), wherein
[0731] R.sup.4 is selected from H, D, F, Cl, CD.sub.3, and methyl;
and
[0732] R.sup.8 is selected H, D, CD.sub.3, CF.sub.3, methyl,
C(O)NR.sup.a1R.sup.a1, C.sub.6-10 aryl, and 4-10 membered
heterocycloalkyl, wherein the C.sub.6-10 aryl and 4-10 membered
heterocycloalkyl are each optionally substituted with 1 or 2
independently selected R.sup.q substituents.
[0733] In some embodiments, the compound is a compound of Formula
(VII), wherein
[0734] R.sup.4 is selected from Cl, CD.sub.3, or methyl;
[0735] R.sup.5 is selected from H or F; and
[0736] R.sup.6 is selected CN, halo or C.sub.1-6 alkyl.
[0737] In some embodiments, the compound is a compound of Formula
(VIII):
##STR00080##
or a pharmaceutically acceptable salt or a tautomer thereof.
[0738] In some embodiments, the compound is a compound of Formula
(VIII), wherein
[0739] R.sup.4 is selected from Cl, CD.sub.3, or methyl;
[0740] R.sup.5 is selected from H or F;
[0741] R.sup.8 is selected H, CF.sub.3 or methyl;
[0742] X.sup.7, X.sup.8, and X.sup.9 are each independently
selected from C, O, N or S; and
[0743] m, n, p are each independently 0, 1, 2, 3 or 4.
[0744] In some embodiments, the compound is a compound of Formula
(IX):
##STR00081##
or a pharmaceutically acceptable salt or a tautomer thereof.
[0745] In some embodiments, the compound is a compound of Formula
(IX), wherein
[0746] R.sup.4 is selected from CD.sub.3, or methyl;
[0747] R.sup.8 is selected H, CF.sub.3 or methyl;
[0748] X.sup.7 is selected from C, O, N or S; and
[0749] N is 0, 1, 2, 3 or 4.
[0750] In some embodiments, the compound is a compound of Formula
(X):
##STR00082##
or a pharmaceutically acceptable salt or a tautomer thereof.
[0751] In some embodiments, the compound is a compound of Formula
(X), wherein
[0752] X.sup.7 is selected from C or O; and
[0753] Nis 1, 2 or 3.
[0754] In some embodiments, the compound is a compound of Formula
(X), wherein
[0755] X.sup.7 is C; and
[0756] N is 1 or 2.
[0757] In some embodiments, the compound or pharmaceutically
acceptable salt of the compound of Formula (I) provided herein is
crystalline. As used herein, "crystalline" or "crystalline form" is
meant to refer to a certain lattice configuration of a crystalline
substance.
[0758] Different crystalline forms of the same substance typically
have different crystalline lattices (e.g., unit cells) which are
attributed to different physical properties that are characteristic
of each of the crystalline forms. In some instances, different
lattice configurations have different water or solvent content.
[0759] Different crystalline forms of the same compound or salt can
have different bulk properties relating to, for example,
hygroscopicity, solubility, stability, and the like. Forms with
high melting points often have good thermodynamic stability which
is advantageous in prolonging shelf-life drug formulations
containing the solid form. Forms with lower melting points often
are less thermodynamically stable, but are advantageous in that
they have increased water solubility, translating to increased drug
bioavailability. Forms that are weakly hygroscopic are desirable
for their stability to heat and humidity and are resistant to
degradation during long storage.
[0760] The different crystalline forms can be identified by solid
state characterization methods such as by X-ray powder diffraction
(XRPD). Other characterization methods such as differential
scanning calorimetry (DSC), thermogravimetric analysis (TGA),
dynamic vapor sorption (DVS), and the like further help identify
the form as well as help determine stability and solvent/water
content.
[0761] An XRPD pattern of reflections (peaks) is typically
considered a fingerprint of a particular crystalline form. It is
well known that the relative intensities of the XRPD peaks can
widely vary depending on, inter alia, the sample preparation
technique, crystal size distribution, various filters used, the
sample mounting procedure, and the particular instrument employed.
In some instances, new peaks may be observed or existing peaks may
disappear, depending on the type of the instrument or the settings.
As used herein, the term "peak" refers to a reflection having a
relative height/intensity of at least about 5% of the maximum peak
height/intensity.
[0762] Moreover, instrument variation and other factors can affect
the 2-theta values. Thus, peak assignments, such as those reported
herein, can vary by plus or minus about 0.2.degree. (2-theta), and
the term "substantially" and "about" as used in the context of XRPD
herein is meant to encompass the above-mentioned variations.
[0763] In the same way, temperature readings in connection with
DSC, TGA, or other thermal experiments can vary about .+-.3.degree.
C. depending on the instrument, particular settings, sample
preparation, etc. Accordingly, a crystalline form reported herein
having a DSC thermogram "substantially" as shown in any of the
Figures or the term "about" is understood to accommodate such
variation.
[0764] The present invention provides crystalline forms of certain
compounds, or salts thereof. In some embodiments, the compound of
Formula I is
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1-
]hexan-1-yl)-4-(methyl-d.sub.3)benzenesulfonamide, or a
pharmaceutically acceptable salt thereof.
[0765] In some embodiments, the present invention provides
crystalline
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexa-
n-1-yl)-4-(methyl-d.sub.3)benzenesulfonamide characterized, for
example, by an XRPD profile substantially as shown in FIG. 1.
[0766] In some embodiments, crystalline
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexa-
n-1-yl)-4-(methyl-d.sub.3)benzenesulfonamide has at least one, at
least two, at least three, at least four, or at least five XRPD
peaks, in terms of 2-theta, selected from about 8.4.degree., about
15.3.degree., about 16.9.degree., about 17.3.degree., about
17.4.degree., about 17.6.degree., about 19.4.degree., about
20.6.degree., about 24.9.degree., and about 26.5.degree..
[0767] In some embodiments, crystalline
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexa-
n-1-yl)-4-(methyl-d.sub.3)benzenesulfonamide is characterized by a
DSC thermogram having an endothermic peak at about 234.degree.
C.
[0768] In some embodiments, crystalline
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexa-
n-1-yl)-4-(methyl-d.sub.3)benzenesulfonamide is characterized by a
thermographic analysis (TGA) substantially as shown in FIG. 3.
[0769] In some embodiments, the
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexa-
n-1-yl)-4-(methyl-d.sub.3)benzenesulfonamide can be isolated as a
hydrochloric acid salt, which can be crystalline.
[0770] In some embodiments, the crystalline form of the
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexa-
n-1-yl)-4-(methyl-d.sub.3)benzenesulfonamide hydrochloric acid salt
has an XRPD profile substantially as shown in FIG. 4.
[0771] In some embodiments, the crystalline form of the
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexa-
n-1-yl)-4-(methyl-d.sub.3)benzenesulfonamide hydrochloric acid salt
has at least one, at least two, at least three, at least four, or
at least five XRPD peaks, in terms of 2-theta, selected from about
9.9.degree., about 13.4.degree., about 14.10, about 15.8.degree.,
about 16.10, about 16.2.degree., about 17.4.degree., about
18.0.degree., about 21.7.degree., about 22.0.degree., about
22.4.degree., about 23.4.degree., about 24.5.degree., about
25.3.degree., about 26.4.degree., about 26.8.degree., and about
27.9.degree..
[0772] In some embodiments, the crystalline form of the
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexa-
n-1-yl)-4-(methyl-d.sub.3)benzenesulfonamide hydrochloric acid salt
has at least one, at least two, at least three, at least four, or
at least five XRPD peaks, in terms of 2-theta, selected from about
9.9.degree., about 13.4.degree., about 14.10, about 15.8.degree.,
about 16.10, about 16.2.degree., about 17.4.degree., about
18.0.degree., about 21.7.degree., about 22.0.degree., about
26.8.degree., and about 27.9.degree..
[0773] In some embodiments, the crystalline form of the
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexa-
n-1-yl)-4-(methyl-d.sub.3)benzenesulfonamide hydrochloric acid salt
is characterized by a DSC thermogram having an endothermic peak at
about 233.4.degree. C.
[0774] In some embodiments, the crystalline form of the
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexa-
n-1-yl)-4-(methyl-d.sub.3)benzenesulfonamide hydrochloric acid salt
is characterized by a thermographic analysis (TGA) substantially as
shown in FIG. 6.
[0775] In some embodiments, the
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexa-
n-1-yl)-4-(methyl-d.sub.3)benzenesulfonamide can be isolated as a
benzenesulfonic acid salt, which can be crystalline.
[0776] In some embodiments, the crystalline form of the
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexa-
n-1-yl)-4-(methyl-d.sub.3)benzenesulfonamide benzenesulfonic acid
salt has an XRPD profile substantially as shown in FIG. 7.
[0777] In some embodiments, the crystalline form of the
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexa-
n-1-yl)-4-(methyl-d.sub.3)benzenesulfonamide benzenesulfonic acid
salt has at least one, at least two, at least three, at least four,
or at least five XRPD peaks, in terms of 2-theta, selected from
about 14.8.degree., about 15.8.degree., about 16.5.degree., about
16.7.degree., about 17.1.degree., about 18.6.degree., about
18.9.degree., about 19.2.degree., about 19.8.degree., about
22.2.degree., about 22.8.degree., about 23.6.degree., about
24.5.degree., about 24.9.degree., and about 25.9.degree..
[0778] In some embodiments, the crystalline form of the
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexa-
n-1-yl)-4-(methyl-d.sub.3)benzenesulfonamide benzenesulfonic acid
salt is characterized by a DSC thermogram having an endothermic
peak at about 213.8.degree. C.
[0779] In some embodiments, the crystalline form of the
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexa-
n-1-yl)-4-(methyl-d.sub.3)benzenesulfonamide benzenesulfonic acid
salt is characterized by a thermographic analysis (TGA)
substantially as shown in FIG. 9.
[0780] It is further appreciated that certain features of the
invention, which are, for clarity, described in the context of
separate embodiments, can also be provided in combination in a
single embodiment. Conversely, various features of the invention
which are, for brevity, described in the context of a single
embodiment, can also be provided separately or in any suitable
subcombination.
[0781] The term "n-membered" where n is an integer typically
describes the number of ring-forming atoms in a moiety where the
number of ring-forming atoms is n. For example, piperidinyl is an
example of a 6-membered heterocycloalkyl ring, pyrazolyl is an
example of a 5-membered heteroaryl ring, pyridyl is an example of a
6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is
an example of a 10-membered cycloalkyl group.
[0782] As used herein, the phrase "optionally substituted" means
unsubstituted or substituted.
[0783] The substituents are independently selected, and
substitution may be at any chemically accessible position. As used
herein, the term "substituted" means that a hydrogen atom is
removed and replaced by a substituent. A single divalent
substituent, e.g., oxo, can replace two hydrogen atoms. It is to be
understood that substitution at a given atom is limited by
valency.
[0784] Throughout the definitions, the term "C.sub.n-m" indicates a
range which includes the endpoints, wherein n and m are integers
and indicate the number of carbons. Examples include C.sub.1-4,
C.sub.1-6, and the like.
[0785] As used herein, the term "C.sub.n-m alkyl", employed alone
or in combination with other terms, refers to a saturated
hydrocarbon group that may be straight-chain or branched, having n
to m carbons. Examples of alkyl moieties include, but are not
limited to, chemical groups such as methyl, ethyl, n-propyl,
isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higher
homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl,
1,2,2-trimethylpropyl, and the like. In some embodiments, the alkyl
group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms,
from 1 to 3 carbon atoms, or 1 to 2 carbon atoms.
[0786] As used herein, "C.sub.n-m alkenyl" refers to an alkyl group
having one or more double carbon-carbon bonds and having n to m
carbons. Example alkenyl groups include, but are not limited to,
ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the
like. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to
4, or 2 to 3 carbon atoms.
[0787] As used herein, "C.sub.n-m alkynyl" refers to an alkyl group
having one or more triple carbon-carbon bonds and having n to m
carbons. Example alkynyl groups include, but are not limited to,
ethynyl, propyn-1-yl, propyn-2-yl, and the like. In some
embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3
carbon atoms.
[0788] As used herein, the term "C.sub.n-m alkylene", employed
alone or in combination with other terms, refers to a divalent
alkyl linking group having n to m carbons. Examples of alkylene
groups include, but are not limited to, ethan-1,1-diyl,
ethan-1,2-diyl, propan-1,1,-diyl, propan-1,3-diyl, propan-1,2-diyl,
butan-1,4-diyl, butan-1,3-diyl, butan-1,2-diyl,
2-methyl-propan-1,3-diyl, and the like. In some embodiments, the
alkylene moiety contains 2 to 6, 2 to 4, 2 to 3, 1 to 6, 1 to 4, or
1 to 2 carbon atoms.
[0789] As used herein, the term "C.sub.n-m alkoxy", employed alone
or in combination with other terms, refers to a group of formula
--O-alkyl, wherein the alkyl group has n to m carbons. Example
alkoxy groups include, but are not limited to, methoxy, ethoxy,
propoxy (e.g., n-propoxy and isopropoxy), butoxy (e.g., n-butoxy
and tert-butoxy), and the like. In some embodiments, the alkyl
group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
[0790] As used herein, the term "C.sub.n-m alkylamino" refers to a
group of formula --NH(alkyl), wherein the alkyl group has n to m
carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to
4, or 1 to 3 carbon atoms. Examples of alkylamino groups include,
but are not limited to, N-methylamino, N-ethylamino, N-propylamino
(e.g., N-(n-propyl)amino and N-isopropylamino), N-butylamino (e.g.,
N-(n-butyl)amino and N-(tert-butyl)amino), and the like.
[0791] As used herein, the term "amino" refers to a group of
formula --NH.sub.2.
[0792] As used herein, the term "aryl," employed alone or in
combination with other terms, refers to an aromatic hydrocarbon
group, which may be monocyclic or polycyclic (e.g., having 2, 3 or
4 fused rings). The term "C.sub.n-m aryl" refers to an aryl group
having from n to m ring carbon atoms. Aryl groups include, e.g.,
phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and
the like. In some embodiments, aryl groups have from 6 to 10 carbon
atoms. In some embodiments, the aryl group is phenyl or
naphthyl.
[0793] As used herein, the term "di(C.sub.n-m alkyl)amino" refers
to a group of formula --N(alkyl).sub.2, wherein the two alkyl
groups each has, independently, n to m carbon atoms. In some
embodiments, each alkyl group independently has 1 to 6, 1 to 4, or
1 to 3 carbon atoms.
[0794] As used herein, "halo" refers to F, Cl, Br, or I. In some
embodiments, a halo is F, Cl, or Br.
[0795] As used herein, "C.sub.n-m haloalkoxy" refers to a group of
formula --O-haloalkyl having n to m carbon atoms. An example
haloalkoxy group is OCF.sub.3. In some embodiments, the haloalkoxy
group is fluorinated only. In some embodiments, the alkyl group has
1 to 6, 1 to 4, or 1 to 3 carbon atoms.
[0796] As used herein, the term "C.sub.n-m haloalkyl", employed
alone or in combination with other terms, refers to an alkyl group
having from one halogen atom to 2s+1 halogen atoms which may be the
same or different, where "s" is the number of carbon atoms in the
alkyl group, wherein the alkyl group has n to m carbon atoms. In
some embodiments, the haloalkyl group is fluorinated only. In some
embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon
atoms.
[0797] As used herein, "cycloalkyl" refers to non-aromatic cyclic
hydrocarbons including cyclized alkyl and/or alkenyl groups.
Cycloalkyl groups can include mono- or polycyclic (e.g., having 2,
3 or 4 fused rings) groups, spirocycles, and bridged rings.
Ring-forming carbon atoms of a cycloalkyl group can be optionally
substituted by oxo or sulfido (e.g., C(O) or C(S)). Also included
in the definition of cycloalkyl are moieties that have one or more
aromatic rings fused (i.e., having a bond in common with) to the
cycloalkyl ring, for example, benzo or thienyl derivatives of
cyclopentane, cyclohexane, and the like. A cycloalkyl group
containing a fused aromatic ring can be attached through any
ring-forming atom including a ring-forming atom of the fused
aromatic ring. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, or
10 ring-forming carbons (C.sub.3-10). In some embodiments, the
cycloalkyl is a C.sub.3-10 monocyclic or bicyclic cyclocalkyl. In
some embodiments, the cycloalkyl is a C3-7 monocyclic cyclocalkyl.
In some embodiments, the cycloalkyl is a C.sub.4-10 spirocycle or
bridged cycloalkyl. Example cycloalkyl groups include cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl,
cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl,
norpinyl, norcarnyl, cubane, adamantane, bicyclo[1.1.1]pentyl,
bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptanyl,
bicyclo[3.1.1]heptanyl, bicyclo[2.2.2]octanyl, spiro[3.3]heptanyl,
and the like. In some embodiments, cycloalkyl is cyclopropyl,
cyclobutyl, cyclopentyl, or cyclohexyl.
[0798] As used herein, "heteroaryl" refers to a monocyclic or
polycyclic aromatic heterocycle having at least one heteroatom ring
member selected from sulfur, oxygen, and nitrogen. In some
embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring
members independently selected from nitrogen, sulfur and oxygen. In
some embodiments, any ring-forming N in a heteroaryl moiety can be
an N-oxide. In some embodiments, the heteroaryl is a 5-10 membered
monocyclic or bicyclic heteroaryl having 1, 2, 3 or 4 heteroatom
ring members independently selected from nitrogen, sulfur and
oxygen. In some embodiments, the heteroaryl is a 5-6 monocyclic
heteroaryl having 1 or 2 heteroatom ring members independently
selected from nitrogen, sulfur and oxygen. In some embodiments, the
heteroaryl is a five-membered or six-membered heteroaryl ring. A
five-membered heteroaryl ring is a heteroaryl with a ring having
five ring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms
are independently selected from N, O, and S. Exemplary
five-membered ring heteroaryls are thienyl, furyl, pyrrolyl,
imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl,
isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl,
1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl,
1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and
1,3,4-oxadiazolyl. A six-membered heteroaryl ring is a heteroaryl
with a ring having six ring atoms wherein one or more (e.g., 1, 2,
or 3) ring atoms are independently selected from N, O, and S.
Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl,
pyrimidinyl, triazinyl and pyridazinyl.
[0799] As used herein, "heterocycloalkyl" refers to non-aromatic
monocyclic or polycyclic heterocycles having one or more
ring-forming heteroatoms selected from O, N, or S. Included in
heterocycloalkyl are monocyclic 4-14-membered heterocycloalkyl
groups. Heterocycloalkyl groups can also include spirocycles and
bridged rings, e.g., a 5-8 membered bridged heterocycloalkyl ring
optionally substituted with 0 to 2 additional heteroatoms
independently selected from nitrogen, oxygen and sulfur. Example
heterocycloalkyl groups include pyrrolidin-2-one,
1,3-isoxazolidin-2-one, pyranyl, tetrahydropuran, oxetanyl,
azetidinyl, morpholino, thiomorpholino, piperazinyl,
tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl,
isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl,
thiazolidinyl, imidazolidinyl, azepanyl, benzazapene,
azabicyclo[3.1.0]hexanyl, diazabicyclo[3.1.0]hexanyl,
oxabicyclo[2.1.1]hexanyl, azabicyclo[2.2.1]heptanyl,
diazabicyclo[2.2.1]heptanyl, azabicyclo[3.1.1]heptanyl,
diazabicyclo[3.1.1]heptanyl, azabicyclo[3.2.1]octanyl,
diazabicyclo[3.2.1]octanyl, oxabicyclo[2.2.2]octanyl,
azabicyclo[2.2.2]octanyl, azaadamantanyl, diazaadamantanyl,
oxa-adamantanyl, azaspiro[3.3]heptanyl, diazaspiro[3.3]heptanyl,
oxa-azaspiro[3.3]heptanyl, azaspiro[3.4]octanyl,
diazaspiro[3.4]octanyl, oxa-azaspiro[3.4]octanyl,
azaspiro[2.5]octanyl, diazaspiro[2.5]octanyl, azaspiro[4.4]nonanyl,
diazaspiro[4.4]nonanyl, oxa-azaspiro[4.4]nonanyl,
azaspiro[4.5]decanyl, diazaspiro[4.5]decanyl,
diazaspiro[4.4]nonanyl, oxa-diazaspiro[4.4]nonanyl and the like.
Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl
group can be optionally substituted by oxo or sulfido (e.g., C(O),
S(O), C(S), or S(O).sub.2, etc.). The heterocycloalkyl group can be
attached through a ring-forming carbon atom or a ring-forming
heteroatom. In some embodiments, the heterocycloalkyl group
contains 0 to 3 double bonds. In some embodiments, the
heterocycloalkyl group contains 0 to 2 double bonds.
[0800] Also included in the definition of heterocycloalkyl are
moieties that have one or more aromatic rings fused (i.e., having a
bond in common with) to the cycloalkyl ring, for example, benzo or
thienyl derivatives of piperidine, morpholine, azepine, etc. A
heterocycloalkyl group containing a fused aromatic ring can be
attached through any ring-forming atom including a ring-forming
atom of the fused aromatic ring. In some embodiments, the
heterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl
having 1 or 2 heteroatoms independently selected from nitrogen,
oxygen, or sulfur and having one or more oxidized ring members. In
some embodiments, the heterocycloalkyl is a monocyclic or bicyclic
4-10 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms
independently selected from nitrogen, oxygen, or sulfur and having
one or more oxidized ring members.
[0801] At certain places, the definitions or embodiments refer to
specific rings (e.g., an azetidine ring, a pyridine ring, etc.).
Unless otherwise indicated, these rings can be attached to any ring
member provided that the valency of the atom is not exceeded. For
example, an azetidine ring may be attached at any position of the
ring, whereas a pyridin-3-yl ring is attached at the
3-position.
[0802] As used herein, the term "oxo" refers to an oxygen atom
(i.e., .dbd.O) as a divalent substituent, forming a carbonyl group
when attached to a carbon (e.g., C.dbd.O), or attached to a
nitrogen or sulfur heteroatom forming a nitroso, sulfinyl or
sulfonyl group.
[0803] The compounds described herein can be asymmetric (e.g.,
having one or more stereocenters). All stereoisomers, such as
enantiomers and diastereomers, are intended unless otherwise
indicated. Compounds of the present invention that contain
asymmetrically substituted carbon atoms can be isolated in
optically active or racemic forms. Methods on how to prepare
optically active forms from optically inactive starting materials
are known in the art, such as by resolution of racemic mixtures or
by stereoselective synthesis. Many geometric isomers of olefins,
C.dbd.N double bonds, and the like can also be present in the
compounds described herein, and all such stable isomers are
contemplated in the present invention. Cis and trans geometric
isomers of the compounds of the present invention are described and
may be isolated as a mixture of isomers or as separated isomeric
forms. In some embodiments, the compound has the (R)-configuration.
In some embodiments, the compound has the (S)-configuration.
[0804] Formulas (I)-(XII) herein include stereoisomers of the
compounds. In some embodiments, the carbon atom to which R.sup.1 is
attached is in the (R)-configuration. In some embodiments, the
carbon atom to which R.sup.1 is attached is in the
(S)-configuration.
[0805] Resolution of racemic mixtures of compounds can be carried
out by any of numerous methods known in the art. An example method
includes fractional recrystallizaion using a chiral resolving acid
which is an optically active, salt-forming organic acid. Suitable
resolving agents for fractional recrystallization methods are, for
example, optically active acids, such as the D and L forms of
tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid,
mandelic acid, malic acid, lactic acid or the various optically
active camphorsulfonic acids such as .beta.-camphorsulfonic acid.
Other resolving agents suitable for fractional crystallization
methods include stereoisomerically pure forms of
.alpha.-methylbenzylamine (e.g., S and R.sup.b forms, or
diastereomerically pure forms), 2-phenylglycinol, norephedrine,
ephedrine, N-methylephedrine, cyclohexylethylamine,
1,2-diaminocyclohexane, and the like.
[0806] Resolution of racemic mixtures can also be carried out by
elution on a column packed with an optically active resolving agent
(e.g., dinitrobenzoylphenylglycine). Suitable elution solvent
composition can be determined by one skilled in the art.
[0807] Compounds provided herein also include tautomeric forms.
Tautomeric forms result from the swapping of a single bond with an
adjacent double bond together with the concomitant migration of a
proton. Tautomeric forms include prototropic tautomers which are
isomeric protonation states having the same empirical formula and
total charge. Example prototropic tautomers include ketone-enol
pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine
pairs, and annular forms where a proton can occupy two or more
positions of a heterocyclic system, for example, 1H- and
3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole,
2-hydroxypyridine and 2-pyridone, and 1H- and 2H-pyrazole.
Tautomeric forms can be in equilibrium or sterically locked into
one form by appropriate substitution.
[0808] All compounds, and pharmaceutically acceptable salts
thereof, can be found together with other substances such as water
and solvents (e.g. hydrates and solvates) or can be isolated.
[0809] In some embodiments, preparation of compounds can involve
the addition of acids or bases to affect, for example, catalysis of
a desired reaction or formation of salt forms such as acid addition
salts.
[0810] Example acids can be inorganic or organic acids and include,
but are not limited to, strong and weak acids. Some example acids
include hydrochloric acid, hydrobromic acid, sulfuric acid,
phosphoric acid, p-toluenesulfonic acid, 4-nitrobenzoic acid,
methanesulfonic acid, benzenesulfonic acid, trifluoroacetic acid,
and nitric acid. Some weak acids include, but are not limited to
acetic acid, propionic acid, butanoic acid, benzoic acid, tartaric
acid, pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid,
nonanoic acid, and decanoic acid.
[0811] Example bases include lithium hydroxide, sodium hydroxide,
potassium hydroxide, lithium carbonate, sodium carbonate, potassium
carbonate, and sodium bicarbonate. Some example strong bases
include, but are not limited to, hydroxide, alkoxides, metal
amides, metal hydrides, metal dialkylamides and arylamines,
wherein; alkoxides include lithium, sodium and potassium salts of
methyl, ethyl and t-butyl oxides; metal amides include sodium
amide, potassium amide and lithium amide; metal hydrides include
sodium hydride, potassium hydride and lithium hydride; and metal
dialkylamides include lithium, sodium, and potassium salts of
methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl,
trimethylsilyl and cyclohexyl substituted amides.
[0812] In some embodiments, the compounds provided herein, or salts
thereof, are substantially isolated. By "substantially isolated" is
meant that the compound is at least partially or substantially
separated from the environment in which it was formed or detected.
Partial separation can include, for example, a composition enriched
in the compounds provided herein. Substantial separation can
include compositions containing at least about 50%, at least about
60%, at least about 70%, at least about 80%, at least about 90%, at
least about 95%, at least about 97%, or at least about 99% by
weight of the compounds provided herein, or salt thereof. Methods
for isolating compounds and their salts are routine in the art.
[0813] The term "compound" as used herein is meant to include all
stereoisomers, geometric isomers, tautomers, and isotopes of the
structures depicted. Compounds herein identified by name or
structure as one particular tautomeric form are intended to include
other tautomeric forms unless otherwise specified.
[0814] The phrase "pharmaceutically acceptable" is employed herein
to refer to those compounds, materials, compositions, and/or dosage
forms which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of human beings and
animals without excessive toxicity, irritation, allergic response,
or other problem or complication, commensurate with a reasonable
benefit/risk ratio.
[0815] The present application also includes pharmaceutically
acceptable salts of the compounds described herein. The present
invention also includes pharmaceutically acceptable salts of the
compounds described herein. As used herein, "pharmaceutically
acceptable salts" refers to derivatives of the disclosed compounds
wherein the parent compound is modified by converting an existing
acid or base moiety to its salt form. Examples of pharmaceutically
acceptable salts include, but are not limited to, mineral or
organic acid salts of basic residues such as amines; alkali or
organic salts of acidic residues such as carboxylic acids; and the
like. The pharmaceutically acceptable salts of the present
invention include the conventional non-toxic salts of the parent
compound formed, for example, from non-toxic inorganic or organic
acids. The pharmaceutically acceptable salts of the present
invention can be synthesized from the parent compound which
contains a basic or acidic moiety by conventional chemical methods.
Generally, such salts can be prepared by reacting the free acid or
base forms of these compounds with a stoichiometric amount of the
appropriate base or acid in water or in an organic solvent, or in a
mixture of the two; generally, non-aqueous media like ether, ethyl
acetate, alcohols (e.g., methanol, ethanol, iso-propanol, or
butanol) or acetonitrile (ACN) are preferred. Lists of suitable
salts are found in Remington's Pharmaceutical Sciences, 17th ed.,
Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of
Pharmaceutical Science, 66, 2 (1977), each of which is incorporated
herein by reference in its entirety.
Synthesis
[0816] As will be appreciated, the compounds provided herein,
including salts and stereoisomers thereof, can be prepared using
known organic synthesis techniques and can be synthesized according
to any of numerous possible synthetic routes.
[0817] Compounds of Formula (I) can be prepared from optionally
protected (e.g., P=acetyl) bicycles 1-1 where Y.sup.1 is halogen
(e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) as shown
in Scheme I. Bicycle 1-1 can be coupled with 1-2, where M.sup.1 is
a boronic acid, boronate ester, potassium trifluoroborate, or an
appropriately substituted metal, such as Sn(Bu).sub.3 or Zn, under
standard Suzuki conditions (e.g., in the presence of a palladium
catalyst, such as tetrakis(triphenylphosphine)palladium(O) or
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II),
complex with dichloromethane and a base (e.g., a carbonate base))
or standard Stille conditions (e.g., in the presence of a
palladium(O) catalyst, such as
tetrakis(triphenylphosphine)palladium(O)) or standard Negishi
conditions (e.g., in the presence of a palladium catalyst, such as
tetrakis(triphenylphosphine)palladium(O) or
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to
give compound 1-3. After coupling, optionally chosen protecting
groups can be removed under conditions suitable for their removal
that are also compatible with the functionality present in 1-3
(e.g., exposure to aqueous HCl) to afford the resulting compounds
of Formula (I).
[0818] Alternatively, the Y.sup.1 group can be converted to an
appropriate substituted metal 1-4 (e.g., M.sup.2 is B(OH).sub.2,
Bpin, BF.sub.3K, Sn(Bu).sub.3, or Zn) and then coupled to 1-5 where
Y.sup.2 is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf
or OMs) under standard Suzuki conditions (e.g., in the presence of
a palladium catalyst, such as
tetrakis(triphenylphosphine)palladium(O) or
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II),
complex with dichloromethane and a base (e.g., a carbonate base))
or standard Stille conditions (e.g., in the presence of a
palladium(O) catalyst, such as
tetrakis(triphenylphosphine)palladium(O)) or standard Negishi
conditions (e.g., in the presence of a palladium(O) catalyst, such
as tetrakis(triphenylphosphine)palladium(O) or
[1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (II)) to
give to give compound 1-3. After coupling, optionally chosen
protecting groups can be removed under conditions suitable for
their removal that are also compatible with the functionality
present in 1-3 (e.g., exposure to aqueous HCl) to afford the
resulting compounds of Formula (I).
##STR00083##
[0819] Intermediates for making compounds of the invention can be
prepared as shown in Scheme II. For example, sulfonyl halide 2-1,
where Y.sup.3 is a halogen (e.g., Cl or F), can be coupled with an
amine 2-2 by various methods (e.g. treatment with an appropriate
base such as pyridine or trimethylamine and optionally with a
catalyst such as 4-dimethylaminopyridine). The Y.sup.2 halo (e.g.,
Cl, Br, or I) or pseudohalo group (e.g., OTf or OMs) of sulfonamide
2-3 can be converted to an appropriate substituted metal 2-4 (e.g.,
M.sup.2 is B(OH).sub.2, Bpin, BF.sub.3K, Sn(Bu).sub.3, or Zn) under
standard conditions (e.g., in the presence of a diboron reagent
such as bis(pinacolato)diboron, a palladium catalyst, such as
dichloro[bis(triphenylphosphoranyl)]palladium or
bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with
dichloromethane, and a base, such as potassium acetate). Compounds
of the invention can be synthesized from intermediates 2-4 using
the methods described in Scheme I.
##STR00084##
[0820] Intermediates for making compounds of the invention can be
prepared as shown in Scheme III. For example, an amine 3-1 can be
coupled with a sulfonyl halide 3-2, where Y.sup.4 is a halogen
(e.g., Cl or F), by various methods (e.g. treatment with an
appropriate base such as pyridine). The Y.sup.2 halo (e.g., Cl, Br,
or I) or pseudohalo group (e.g., OTf or OMs) of sulfonamide 3-3 can
be converted to an appropriate substituted metal 3-4 (e.g., M.sup.2
is B(OH).sub.2, Bpin, BF.sub.3K, Sn(Bu).sub.3, or Zn) under
standard conditions (e.g., in the presence of a diboron reagent
such as bis(pinacolato)diboron, a palladium catalyst, such as
dichloro[bis(triphenylphosphoranyl)]palladium or
bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with
dichloromethane, and a base, such as potassium acetate). Compounds
of the invention can be synthesized from intermediates 3-4 using
the methods described in Scheme I.
##STR00085##
[0821] Intermediates for making compounds of the invention can be
prepared as shown in Scheme IV. For example, an aryl halide 4-1 can
be converted to organometallic reagent 4-2 where M.sup.3 is a metal
(e.g., MgY.sup.a where Y.sup.a is a halide) under standard
conditions (e.g., in the presence of magnesium and optionally an
additive such as 1,2-dibromoethane or lithium chloride). The
resulting organometallic reagent 4-2 can be converted to the
sulfinate 4-3 under standard conditions (e.g., quenching with
sulfur dioxide or 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide)
adduct) and then alkylated with reagent 4-4 where Y.sup.9 is a halo
group (e.g., Cl, Br, or I) or other leaving group (e.g., OMs or
OTs) to give the sulfone 4-5. Halogenation with suitable reagents,
such as N-chlorosuccinimide, N-bromosuccinimide, Br.sub.2, or
N-iodosuccinimide can give halide 4-6 where Y.sup.2 is a halo group
(e.g., Cl, Br, or I). The Y.sup.2 halo can be converted to an
appropriate substituted metal (e.g., M.sup.2 is B(OH).sub.2, Bpin,
BF.sub.3K, Sn(Bu).sub.3, or Zn) under standard conditions (e.g., in
the presence of a diboron reagent such as bis(pinacolato)diboron, a
palladium catalyst, such as
dichloro[bis(triphenylphosphoranyl)]palladium or
bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with
dichloromethane, and a base, such as potassium acetate) to give
4-7.
[0822] Alternatively, an aryl halide 4-1 can be directly converted
to the sulfonate 4-3 under standard metal-catalyzed conditions
(e.g., in the presence of a sulfur dioxide donor, such as potassium
metabisulfite, a palladium catalyst such as palladium acetate,
ligands such as triphenylphosphine and 1,10-phenathroline, and a
base (e.g., sodium formate)) and then alkylated with reagent 4-4
where Y.sup.9 is a halo group (e.g., Cl, Br, or I) or other leaving
group (e.g., OMs or OTs) to give the sulfone 4-5. The sulfone 4-5
can be halogenated and then metalated to give 4-7. Compounds of the
invention can be synthesized from intermediates 4-4 using the
methods described in Scheme I.
##STR00086##
[0823] Compounds of Formula (I) can also be prepared as shown in
Scheme V. For example, heteroaromatic amine 5-1, where Y.sup.4 is a
halogen (e.g., Cl, Br, or I), can be reacted with alpha-halo
carbonyl derivative 5-2 where Y.sup.5 is a halogen (e.g., Cl or
Br), to give heterocycle 5-3. The amino group of 5-3 can be
optionally protected with a suitable protecting group P, (e.g.,
acetyl), under standard conditions (e.g., in the presence of acetyl
chloride or acetic anhydride, a base (e.g., triethylamine), and
optionally a catalyst (e.g., 4-dimethylaminopyridine)) to give the
protected amine 5-4. Compound 5-4 can be halogenated with suitable
reagents, such as N-chlorosuccinimide, N-bromosuccinimide, or
N-iodosuccinimide, to give halide 5-5 where Y.sup.1 is a halo group
(e.g., Cl, Br, or I). Halide 5-5 can be selectively coupled with
1-2, where M.sup.1 is a boronic acid, boronate ester, potassium
trifluoroborate, or an appropriately substituted metal such as
Sn(Bu).sub.3 or Zn, under standard Suzuki conditions (e.g., in the
presence of a palladium catalyst, such as
tetrakis(triphenylphosphine)palladium(O) and a base (e.g., a
carbonate base)) or standard Stille conditions (e.g., in the
presence of a palladium(O) catalyst, such as
tetrakis(triphenylphosphine)palladium(0)) or standard Negishi
conditions (e.g., in the presence of a palladium catalyst, such as
tetrakis(triphenylphosphine)palladium(0) or
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to
give compound 5-6. Compound 5-6 can be coupled with 5-7, where
M.sup.4 is a boronic acid, boronate ester, potassium
trifluoroborate, or an appropriately substituted metal, such as
Sn(Bu).sub.3 or Zn, under standard Suzuki conditions (e.g., in the
presence of a palladium catalyst, such as
bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with
dichloromethane or
bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)
and a base (e.g., a carbonate base or cesium fluoride)) or standard
Stille conditions (e.g., in the presence of a palladium(0)
catalyst, such as tetrakis(triphenylphosphine)palladium(0)) or
standard Negishi conditions (e.g., in the presence of a palladium
catalyst, such as tetrakis(triphenylphosphine)palladium(0) or
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to
give compound 5-8. The optionally chosen protecting group can be
removed according to Scheme I to afford the resulting compounds of
Formula (I).
[0824] Alternatively, halide 5-5 can be selectively coupled with
5-7, where M.sup.4 is a boronic acid, boronate ester, potassium
trifluoroborate, or an appropriately substituted metal such as
Sn(Bu).sub.3 or Zn, under standard Suzuki conditions (e.g., in the
presence of a palladium catalyst, such as
bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with
dichloromethane or
bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)
and a base (e.g., a carbonate base or cesium fluoride)) or standard
Stille conditions (e.g., in the presence of a palladium(0)
catalyst, such as tetrakis(triphenylphosphine)palladium(0)) or
standard Negishi conditions (e.g., in the presence of a palladium
catalyst, such as tetrakis(triphenylphosphine)palladium(0) or
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to
give compound 5-9, which can be elaborated according to Scheme I to
afford the resulting compounds of Formula (I).
##STR00087##
[0825] Compounds of Formula (I) can also be prepared as shown in
Scheme VI. For example, hetereoaromatic amine 6-1, where Y.sup.4
and Y.sup.6 are halo groups, can be reacted with alpha-halo
carbonyl derivatives 5-2 where Y.sup.5 is a halogen (e.g., Cl or
Br), to give heterocycle 6-2. Halogenation of heterocycle 6-2 with
suitable reagents, such as N-chlorosuccinimide, N-bromosuccinimide,
or N-iodosuccinimide can give halide 6-3 where Y.sup.1 is a halo
group (e.g., Cl, Br, or I). Nucleophilic aromatic substitution of
the halide of 6-3 with amine 6-4 can provide halide 6-5. Halide 6-5
can be selectively coupled with 1-2, where M.sup.1 is a boronic
acid, boronate ester, potassium trifluoroborate, or an
appropriately substituted metal such as Sn(Bu).sub.3 or Zn, under
standard Suzuki conditions (e.g., in the presence of a palladium
catalyst, such as tetrakis(triphenylphosphine)palladium(0) and a
base (e.g., a carbonate base)) or standard Stille conditions (e.g.,
in the presence of a palladium(0) catalyst, such as
tetrakis(triphenylphosphine)palladium(0)) or standard Negishi
conditions (e.g., in the presence of a palladium catalyst, such as
tetrakis(triphenylphosphine)palladium(0) or
[1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (II)), to
give compound 6-6. Coupling of compound 6-6 with 6-7, where M.sup.4
is a boronic acid, boronate ester, potassium trifluoroborate, or an
appropriately substituted metal such as Sn(Bu).sub.3 or Zn, under
standard Suzuki conditions (e.g., in the presence of a palladium
catalyst, such as
bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with
dichloromethane or
bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)
and a base (e.g., a carbonate base or cesium fluoride)) or standard
Stille conditions (e.g., in the presence of a palladium(0)
catalyst, such as tetrakis(triphenylphosphine)palladium(0)) or
standard Negishi conditions (e.g., in the presence of a palladium
catalyst, such as tetrakis(triphenylphosphine)palladium(0) or
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)), can
afford the resulting compounds of Formula (I).
[0826] Alternatively, selective coupling of halide 6-5 with 6-7,
under standard Suzuki conditions (e.g., in the presence of a
palladium catalyst, such as
bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with
dichloromethane or
bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)
and a base (e.g., a carbonate base or cesium fluoride)) or standard
Stille conditions (e.g., in the presence of a palladium(0)
catalyst, such as tetrakis(triphenylphosphine)palladium(0)) or
standard Negishi conditions (e.g., in the presence of a palladium
catalyst, such as tetrakis(triphenylphosphine)palladium(0) or
[1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (II)), can
afford compound 6-8, which can be further reacted according to
Scheme I to afford the resulting compounds of Formula (I).
##STR00088##
[0827] Compounds of Formula (I) can also be prepared as shown in
Scheme VII. For example, hetereoaromatic amine 7-1, where Y.sup.6
is a halogen group, can be reacted with alpha-halo carbonyl
derivatives 5-2 where Y.sup.5 is a halogen (e.g., Cl or Br), to
give heterocycle 7-2. Halogenation of heterocycle 7-2 with suitable
reagents, such as N-chlorosuccinimide, N-bromosuccinimide, or
N-iodosuccinimide, can give halide 7-3 where Y.sup.1 is a halo
group (e.g., Cl, Br, or I). Nucleophilic aromatic substitution of
the halide 7-3 with amine 7-4 can provide halide 7-5. Halide 7-5
can be further reacted according to Scheme I to afford the
resulting compounds of Formula (I).
##STR00089##
[0828] Compounds of Formula (I) can also be prepared as shown in
Scheme VIII. For example, hetereoaromatic amine 8-1, where Y.sup.7
is a halogen group, can be reacted with alpha-halo carbonyl
derivatives 5-2 where Y.sup.5 is a halogen (e.g., Cl or Br), to
give heterocycle 8-3. The amino group of 8-3 can be optionally
protected with a suitable protecting group P (e.g., acetyl), under
standard conditions (e.g., in the presence of acetyl chloride or
acetic anhydride, a base (e.g., triethylamine), and optionally a
catalyst (e.g., 4-dimethylaminopyridine)) to give protected amine
8-4. Compound 8-4 can be halogenated with suitable reagents, such
as N-chlorosuccinimide, N-bromosuccinimide, or N-iodosuccinimide,
to give a halide 8-5 where Y.sup.1 is a halo group (e.g., Cl, Br,
or I). Halide 8-5 can be selectively coupled with 1-2, where
M.sup.1 is a boronic acid, boronate ester, potassium
trifluoroborate, or an appropriately substituted metal such as
Sn(Bu).sub.3 or Zn, under standard Suzuki conditions (e.g., in the
presence of a palladium catalyst, such as
tetrakis(triphenylphosphine)palladium(0) and a base (e.g., a
carbonate base)) or standard Stille conditions (e.g., in the
presence of a palladium(0) catalyst, such as
bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with
dichloromethane) or standard Negishi conditions (e.g., in the
presence of a palladium catalyst, such as
tetrakis(triphenylphosphine)palladium(0) or
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to
give compound 8-6. Coupling of compound 8-6 with 8-7, where M.sup.5
is a boronic acid, boronate ester, potassium trifluoroborate, or an
appropriately substituted metal such as Sn(Bu).sub.3 or Zn, under
standard Suzuki conditions (e.g., in the presence of a palladium
catalyst, such as
bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)
and a base (e.g., cesium fluoride)) or standard Stille conditions
(e.g., in the presence of a palladium(0) catalyst, such as
tetrakis(triphenylphosphine)palladium(0)) or standard Negishi
conditions (e.g., in the presence of a palladium catalyst, such as
tetrakis(triphenylphosphine)palladium(0) or
[1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (II)), can
give compound 8-8. The optionally chosen protecting group can be
removed according to Scheme I to afford the resulting compounds of
Formula (I).
[0829] Alternatively, halide 8-5 can be selectively coupled with
8-7, where M.sup.4 is a boronic acid, boronate ester, potassium
trifluoroborate, or an appropriately substituted metal such as
Sn(Bu).sub.3 or Zn, under standard Suzuki conditions (e.g., in the
presence of a palladium catalyst, such as
bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)
and a base (e.g cesium fluoride)) or standard Stille conditions
(e.g., in the presence of a palladium(0) catalyst, such as
tetrakis(triphenylphosphine)palladium(0)) or standard Negishi
conditions (e.g., in the presence of a palladium catalyst, such as
tetrakis(triphenylphosphine)palladium(0) or
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to
give compound 8-9, which can be further reacted according to Scheme
I to afford the resulting compounds of Formula (I).
##STR00090##
[0830] Compounds of Formula (I) can also be prepared as shown in
Scheme IX. Preparation of intermediate 9-7 from imidazole 9-1 can
be achieved by methods analogous to those described in
International App. No. WO 2014/011974, the disclosure of which is
incorporated herein by reference in its entirety. Amination under
standard conditions (e.g., in the presence of an NH.sub.2-transfer
agent such as chloramine, O-(diphenylphosphinyl)hydroxylamine, or
O-(4-nitrobenzoyl)hydroxylamine and a base such as sodium hydride,
lithium hexamethyldisilazane, or potassium tert-butoxide) and then
condensation with an alkyl chloroformate ClCO.sub.2R.sup.13, where
R.sup.13 is an alkyl group, under standard conditions (e.g.
treatment with an appropriate base such as pyridine) can give
compound 9-2. Cyclization of 9-2 in the presence of ammonia can
provide bicycle 9-3. The bicycle 9-3 can be halogenated with
suitable reagents, such as N-chlorosuccinimide, N-bromosuccinimide,
or N-iodosuccinimide, to give a halide 9-4 where Y.sup.1 is a halo
group (e.g., Cl, Br, or I). Dehydrative halogenation (e.g., by
treating with a reagent such as POCl.sub.3 or POBr.sub.3) can
afford compound 9-5, where Y.sup.4 and Y.sup.6 are each halogens
(e.g., Cl or Br). Nucleophilic aromatic substitution of the halide
of 9-5 with amine 9-6 can provide intermediate 9-7.
[0831] Intermediate 9-7 can be selectively coupled with 1-2, where
M.sup.1 is a boronic acid, boronate ester, potassium
trifluoroborate, or an appropriately substituted metal such as
Sn(Bu).sub.3 or Zn, under standard Suzuki conditions (e.g., in the
presence of a palladium catalyst, such as
tetrakis(triphenylphosphine)palladium(O) and a base (e.g., a
carbonate base)) or standard Stille conditions (e.g., in the
presence of a palladium(O) catalyst, such as
tetrakis(triphenylphosphine)palladium(O)) or standard Negishi
conditions (e.g., in the presence of a palladium catalyst, such as
tetrakis(triphenylphosphine)palladium(O) or
[1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (II)), to
give compound 9-8. Coupling of compound 9-8 with 9-9, where M.sup.4
is a boronic acid, boronate ester, potassium trifluoroborate, or an
appropriately substituted metal such as Sn(Bu).sub.3 or Zn, under
standard Suzuki conditions (e.g., in the presence of a palladium
catalyst, such as
bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with
dichloromethane or
bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)
and a base (e.g., a carbonate base or cesium fluoride)) or standard
Stille conditions (e.g., in the presence of a palladium(O)
catalyst, such as tetrakis(triphenylphosphine)palladium(O)) or
standard Negishi conditions (e.g., in the presence of a palladium
catalyst, such as tetrakis(triphenylphosphine)palladium(O) or
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)), can
afford the resulting compounds of Formula (I).
##STR00091## ##STR00092##
[0832] Intermediates for making compounds of the invention can be
prepared as shown in Scheme X. Bis-halogenation of heteroaromatic
amine 10-1 with suitable reagents, such as N-chlorosuccinimide,
N-bromosuccinimide, Br.sub.2, or N-iodosuccinimide can give halide
10-2 where Y.sup.4 and Y.sup.6 are each halogens (e.g., Cl, Br, or
I). Nucleophilic aromatic substitution of halide 10-2 with amine
10-3 can provide compound 10-4. Compounds of the invention can be
synthesized from intermediates 10-2 and 10-4 using the methods
described in Scheme VI and Scheme V, respectively.
##STR00093##
[0833] Intermediates for making compounds of the invention can be
prepared as shown in Scheme XI. Nucleophilic aromatic substitution
of halide 11-1, where Y.sup.4 and Y.sup.8 are each halogens (e.g.,
Cl or Br), with ammonia can provide heteroaromatic amine 11-2.
Halogenation of heteroaromatic amine 11-2 with suitable reagents,
such as N-chlorosuccinimide, N-bromosuccinimide, Br.sub.2, or
N-iodosuccinimide, optionally in the presence of a base, such
sodium bicarbonate or sodium carbonate, can give compound 11-3
where Y.sup.6 is a halo group (e.g., Cl, Br, or I). Nucleophilic
aromatic substitution of compound 11-3 with amine 11-4 can provide
compound 11-5. Compounds of the invention can be synthesized from
intermediates 11-3 and 11-5 using the methods described in Scheme
VI and Scheme V, respectively.
##STR00094##
[0834] Intermediates for making compounds of the invention can be
prepared as shown in Scheme XII. Nucleophilic aromatic substitution
of halide 12-1, where Y.sup.8 is a halogen (e.g., Cl or Br), with
ammonia can provide heteroaromatic amine 12-2. Halogenation of
heteroaromatic amine 12-2 with suitable reagents, such as
N-chlorosuccinimide, N-bromosuccinimide, Br.sub.2, or
N-iodosuccinimide, optionally in the presence of a base, such
sodium bicarbonate or sodium carbonate, can give compound 12-3,
where Y.sup.6 is a halo group (e.g., Cl, Br, or I). Nucleophilic
aromatic substitution of compound 12-3 with amine 12-4 can provide
compound 12-5. Compounds of the invention can be synthesized from
intermediates 12-3 and 12-5 using the methods described in Scheme
VI and Scheme V, respectively.
##STR00095##
[0835] In addition to the synthetic route outlined in Scheme I
(hereinafter referred to as Method A), which uses intermediates 2-4
formed as shown in Scheme II, compounds of Formula (I) can also be
prepared as shown in Scheme X (Method B). In Method B, halide X-1
where Yi is a halogen (e.g., Cl, Br or I) can be coupled with X-2
where M.sup.1 is a boronic acid, boronate ester, potassium
trifluoroborate, or an appropriately substituted metal such as
Sn(Bu).sub.3 or Zn, under standard Suzuki conditions (e.g., in the
presence of a palladium catalyst, such as
tetrakis(triphenylphosphine)palladium(0) and a base (e.g., a
carbonate base)) or standard Stille conditions (e.g., in the
presence of a palladium(0) catalyst, such as
tetrakis(triphenylphosphine)palladium(0)) or standard Negishi
conditions (e.g., in the presence of a palladium catalyst, such as
tetrakis(triphenylphosphine)palladium(0) or
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)), to
give compound X-3. Intermediate X-3 can be treated with
chlorosulfonic acid in a suitable solvent at a temperature ranging
from 0.degree. C. to 50.degree. C. to afford sulfonyl chloride X-4.
Sulfonyl chloride can be reacted with an amine X-5 in the presence
of base (such as triethylamine or Hunig's base) to afford compounds
of Formula (I).
##STR00096##
[0836] Intermediates 1-1 (Scheme I) useful for preparing compounds
of Formula (I) wherein X.sup.2 is N and of varying substitution at
R.sup.b can be prepared via the method shown in Scheme Y.
Condensation of Y-1 with an amidine at elevated temperature (e.g.,
80 to 95.degree. C.) in a suitable solvent (e.g., EtOH) affords
bicyclic intermediate Y-2. Alternatively, Y-1 can be treated with a
nitrile and acid (e.g., HCl) in a suitable solvent (e.g., dioxane)
at elevated temperature (e.g., 100 to 110.degree. C.) to afford
Y-2. In some cases of cyclization the use of nitriles requires that
the reaction mixture is made basic in the second step to facilitate
cyclization. Intermediate Y-2 can be halogenated with suitable
reagents, such as N-chlorosuccinimide, N-bromosuccinimide, Br.sub.2
or N-iodosuccinimide to afford halide Y-3 where Yi is a halo group
(e.g., Cl, Br, or I). Dehydrative halogenation (e.g., by treating
with a reagent such as POCl.sub.3 or POBr.sub.3) can afford
compound Y-4 where Y.sup.6 is a halogen (e.g., Cl or Br).
Nucleophilic aromatic substitution of the halide of Y-4 with
ammonia (e.g., using aq. NH.sub.4OH solution) can provide
intermediates Y-5, useful for preparing compounds of Formula (I).
Alternatively, intermediate Y-3 can be condensed with an amine
R.sup.7NH.sub.2 (e.g., p-methoxybenzylamine) with a coupling
reagent (e.g., BOP) to give intermediate Y-6. Deprotection of Y-6
(e.g., using TFA) can give Y-5.
##STR00097##
[0837] Alternatively, intermediates 1-1 (Scheme I) useful for
preparing compounds of Formula (I) wherein X.sup.2 is N and of
varying substitution at R.sup.b can be prepared via the method
shown in Scheme Y-B. Condensation of Y-7 with an amidine at
elevated temperature (e.g., 80 to 95.degree. C.) in a suitable
solvent (e.g., EtOH) affords bicyclic intermediate Y-8.
Alternatively, Y-7 can be treated with a nitrile and acid (e.g.,
HCl) in a suitable solvent (e.g., dioxane) at elevated temperature
(e.g., 100 to 110.degree. C.) to afford Y-8. In some cases of
cyclization the use of nitriles requires that the reaction mixture
is made basic in the second step to facilitate cyclization.
Intermediate Y-8 can be halogenated with suitable reagents, such as
N-chlorosuccinimide, N-bromosuccinimide, Br.sub.2 or
N-iodosuccinimide to afford intermediates Y-5, useful for preparing
compounds of Formula (I).
##STR00098##
[0838] Substituents at R.sup.g may be introduced following the
procedure shown in Scheme Z. Intermediate Z-1 can be halogenated
with suitable reagents, such as N-chlorosuccinimide,
N-bromosuccinimide, Br.sub.2 or N-iodosuccinimide to afford halide
Z-2 where Y.sup.9 is a halo group (e.g., Cl, Br, or I). The Y.sup.9
halo group of Z-2 can be coupled to R.sup.9-M (Z-3) (e.g., M is
B(OH).sub.2, Bpin, BF.sub.3K, Sn(Bu).sub.3, Zn or Al) under
standard conditions for Suzuki, Stille, Negishi and the like, in
the presence of a palladium catalyst, and where appropriate, a
base, to afford compounds of Formula (I).
##STR00099##
[0839] Substituents at R.sup.4 may be introduced following the
procedure outlined in Scheme Q. Intermediate Q-1 can be selectively
coupled with Q-2 bearing a halogen substituent Y.sup.4 (e.g., Cl)
to afford intermediate Q-3. The Y.sup.4 halo group of Q-3 can be
coupled to R.sup.4-M (Q-4) (e.g., M is B(OH).sub.2, Bpin,
BF.sub.3K, Sn(Bu).sub.3, Zn or Al) under standard conditions for
Suzuki, Stille, Negishi and the like, in the presence of a
palladium catalyst and where appropriate, a base, to afford
compounds of Formula (I).
##STR00100##
[0840] Where not commercially available, optionally protected
("PHN") amines, such as YY-1 wherein X.sup.7 can be N, O, or C and
optionally substituted with 0, 1 or 2 R.sup.b groups; and m, n, p
can independently be 0, 1, 2, 3 or 4, required to prepare compounds
of Formula (I) can be prepared following the steps outlined in
Scheme YY. Carboxylic acid YY-1 can be converted to a primary amide
YY-2 by activation using an alkyl chloroformate (e.g., ethyl
chloroformate) in the presence of a base (e.g., Hunig's base
ortriethylamine) followed by reaction with an ammonia source (e.g.,
aq. NH.sub.4OH solution) to afford primary amide intermediate YY-2.
Alternative activating agents can be used in this transformation
(e.g., thionyl chloride, oxalyl chloride or peptide coupling
reagents such as DCC, or HATU). Primary amide YY-2 can be converted
to nitrile YY-3 using reagents for dehydration (e.g.,
trichloroacetyl chloride, thionyl chloride, trifluoroacetic
anhydride) in the presence of base (e.g., Hunig's base or
triethylamine).
##STR00101##
[0841] Where not commercially available, optionally protected (P)
amines, such as XX-1 wherein X.sup.7 can be N, O, or C and
optionally substituted with 0, 1 or 2 R.sup.b groups; m, n, p can
independently be 0, 1, 2, 3 or 4, and R.sup.b can be alkyl (e.g.,
methyl, ethyl ester) or a leaving group formed by activation with
reagents (e.g., chloroformate), required to prepare compounds of
Formula (I) can also be prepared following the steps outlined in
Scheme XX. Ester XX-1 can be reacted with a nucleophile (e.g., a
Grignard reagent or alkyllithium reagent) to afford alcohol XX-2 or
reduced to afford XX-6. The carboxylic acid XX-3 can be converted
to heterocycles XX-4 by methods known to one skilled in the art.
Alternatively, the carboxylic acid of XX-3 can be converted into
carboxylic amides, XX-5, by treatment with an amine in the presence
of a coupling reagent and base. The carboxylic acid can also give
rise to alcohol XX-6 via reduction. Alcohol XX-6 can be used to
afford fluorinated products such as XX-7 by deoxofluorination or
oxidation to XX-8, followed by deoxofluorination to afford XX-9.
Derivatives such as XX-10 and XX-11 can be prepared by activation
of the alcohol to displacement by conversion to a leaving group
(e.g., Cl, Br, I, OMs or OTs) and carrying out the displacement
with cyanide, amines or heterocycles. Alternatively, optionally
protected amines XX-11 can be prepared by reductive amination of
aldehyde XX-8. Amines such as XX-12 can be functionalized via
reductive amination, acylation and other reactions known to one
skilled in the art, to afford intermediates of type XX-13 which are
useful for preparing compounds of Formula (I). Depending on which
compound of Formula (I) being prepared the R.sup.b groups pending
from XX-1 to XX-13 can be any selected from any of the appropriate
R.sup.b groups as described in this disclosure.
##STR00102##
[0842] Where desired, any of the amines from Scheme YY or Scheme XX
can be used to prepare secondary amines by alkylation before
removal of the protecting group as shown in Scheme XX-B. Suitably
protected amines XX-B-1 can be treated with base (e.g., NaH,
K.sub.2CO.sub.3) and an alkylating agent R'-LG wherein LG is a
leaving group (e.g., Cl, Br, I, OMs or OTs), to afford intermediate
XX-B-2. Deprotection furnishes secondary amines XX-B-3 which are
useful for preparing compounds of Formula (I).
##STR00103##
[0843] The reactions for preparing compounds described herein can
be carried out in suitable solvents which can be readily selected
by one of skill in the art of organic synthesis. Suitable solvents
can be substantially non-reactive with the starting materials
(reactants), the intermediates, or products at the temperatures at
which the reactions are carried out, (e.g., temperatures which can
range from the solvent's freezing temperature to the solvent's
boiling temperature). A given reaction can be carried out in one
solvent or a mixture of more than one solvent. Depending on the
particular reaction step, suitable solvents for a particular
reaction step can be selected by the skilled artisan.
[0844] The expressions, "ambient temperature" and "room
temperature" or "rt" as used herein, are understood in the art, and
refer generally to a temperature, e.g. a reaction temperature, that
is about the temperature of the room in which the reaction is
carried out, for example, a temperature from about 20.degree. C. to
about 30.degree. C.
[0845] Preparation of compounds described herein can involve the
protection and deprotection of various chemical groups. The need
for protection and deprotection, and the selection of appropriate
protecting groups, can be readily determined by one skilled in the
art. The chemistry of protecting groups can be found, for example,
in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic
Synthesis, 3.sup.rd Ed., Wiley & Sons, Inc., New York
(1999).
[0846] Reactions can be monitored according to any suitable method
known in the art. For example, product formation can be monitored
by spectroscopic means, such as nuclear magnetic resonance
spectroscopy (e.g., .sup.1H or .sup.13C), infrared spectroscopy,
spectrophotometry (e.g., UV-visible), mass spectrometry, or by
chromatographic methods such as high performance liquid
chromatography (HPLC), liquid chromatography-mass spectroscopy
(LCMS), or thin layer chromatography (TLC). Compounds can be
purified by those skilled in the art by a variety of methods,
including high performance liquid chromatography (HPLC) and normal
phase silica chromatography.
Methods of Use
[0847] The compounds, salts or stereoisomers thereof described
herein inhibit activity of PI3K.gamma. kinase. Accordingly, the
compounds, salts or stereoisomers described herein can be used in
methods of inhibiting PI3K.gamma. kinase by contacting the kinase
with any one or more of the compounds, salts, or compositions
described herein. In some embodiments, the compounds or salts can
be used in methods of inhibiting activity of PI3K.gamma. in an
individual/patient in need of the inhibition by administering an
effective amount of a compound or salt of described herein. In some
embodiments, modulating is inhibiting. In some embodiments, the
contacting is in vivo. In some embodiments, the contacting is ex
vivo. Advantageously, the compounds as described herein demonstrate
better efficacy and favorable safety and toxicity profiles in
animal studies.
[0848] In some embodiments, the PI3K.gamma. includes a mutation. A
mutation can be a replacement of one amino acid for another, or a
deletion of one or more amino acids. In such embodiments, the
mutation can be present in the kinase domain of the
PI3K.gamma..
[0849] In some embodiments, the compound or salt further inhibits
PI3K.delta..
[0850] The compounds or salts described herein can be selective. By
"selective" is meant that the compound binds to or inhibits
PI3K.gamma. with greater affinity or potency, respectively,
compared to at least one other kinase. In some embodiments, the
compounds of the invention are selective inhibitors of PI3K.gamma.
over PI3K.delta., PI3K.alpha., and PI3K.delta.. In some
embodiments, the compounds of the invention are selective
inhibitors of PI3K.gamma. over PI3K.alpha. and PI3KO. In some
embodiments, selectivity can be at least about 2-fold, 3-fold,
5-fold, 10-fold, at or 20-fold over PI3K.delta. as measured by the
assays described herein. In some embodiments, selectivity can be
tested at the K.sub.m ATP concentration of each enzyme. In some
embodiments, the selectivity of compounds of the invention can be
determined by cellular assays associated with particular PI3K
kinase activity.
[0851] Another aspect of the present invention pertains to methods
of treating a kinase PI3K.gamma.-associated disease or disorder in
an individual (e.g., patient) by administering to the individual in
need of such treatment a therapeutically effective amount or dose
of one or more compounds of the present invention or a
pharmaceutical composition thereof. A PI3K.gamma.-associated
disease or disorder can include any disease, disorder or condition
that is directly or indirectly linked to expression or activity of
the PI3K.gamma., including overexpression and/or abnormal activity
levels.
[0852] In some embodiments, the disease or disorder is an
autoimmune disease or disorder, cancer, cardiovascular disease, or
neurodegenerative disease.
[0853] In some embodiments, the disease or disorder is lung cancer
(e.g., non-small cell lung cancer), melanoma, pancreatic cancer,
breast cancer, prostate cancer, liver cancer, color cancer,
endometrial cancer, bladder cancer, skin cancer, cancer of the
uterus, renal cancer, gastric cancer, or sarcoma. In some
embodiments, the sarcoma is Askin's tumor, sarcoma botryoides,
chondrosarcoma, Ewing's sarcoma, malignant hemangioendothelioma,
malignant schwannoma, osteosarcoma, alveolar soft part sarcoma,
angiosarcoma, cystosarcoma phyllodes, dermatofibrosarcoma
protuberans, desmoid tumor, desmoplastic small round cell tumor,
epithelioid sarcoma, extraskeletal chondrosarcoma, extraskeletal
osteosarcoma, fibrosarcoma, gastrointestinal stromal tumor (GIST),
hemangiopericytoma, hemangiosarcoma, Kaposi's sarcoma,
leiomyosarcoma, liposarcoma, lymphangiosarcoma, lymphosarcoma,
malignant peripheral nerve sheath tumor (MPNST), neurofibrosarcoma,
rhabdomyosarcoma, synovial sarcoma, or undifferentiated pleomorphic
sarcoma.
[0854] In some embodiments, the disease or disorder is acute
myeloid leukemia (e.g., acute monocytic leukemia), small
lymphocyctic lymphoma, chronic lymphocytic leukemia (CLL), chronic
myelogenous leukemia (CML), multiple myeloma, T-cell actute
lymphoblasic leukemia (T-ALL), cutaneous T-cell lymphoma, large
granular lymphocytic leukemia, mature (peripheral) t-cell neoplasm
(PTCL), anaplastic large cell lymphoma (ALCL), or lymphoblastic
lymphoma. In some embodiments, the mature (peripheral) t-cell
neoplasm (PTCL) is T-cell prolymphocytic leukemia, T-cell granular
lymphocytic leukemia, aggressive NK-cell leukemia, mycosis
fungoides/Sezary syndrome, naplastic large cell lymphoma (T-cell
type), enteropathy type T-cell lymphoma, adult T-cell
leukemia/lymphoma, or angioimmunoblastic T-cell lymphoma In some
embodiments, the anaplastic large cell lymphoma (ALCL) is systemic
ALCL or primary cutaneous ALCL.
[0855] In some embodiments, the disease or disorder is Burkitt's
lymphoma, acute myeloblastic leukemia, chronic myeloid leukemia,
non-Hodgkin's lymphoma, Hodgkin's lymphoma, hairy cell leukemia,
Mantle cell lymphoma, small lymphocytic lymphoma, follicular
lymphoma, xenoderoma pigmentosum, keratoctanthoma,
lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma,
Waldenstrom's macroglobulinemia, prolymphocytic leukemia, acute
lymphoblastic leukemia, myelofibrosis, mucosa-associated lymphatic
tissue (MALT) lymphoma, mediastinal (thymic) large B-cell lymphoma,
lymphomatoid granulomatosis, splenic marginal zone lymphoma,
primary effusion lymphoma, intravascular large B-cell lymphoma,
plasma cell leukemia, extramedullary plasmacytoma, smouldering
myeloma (aka asymptomatic myeloma), monoclonal gammopathy of
undetermined significance (MGUS), or diffuse large B cell
lymphoma.
[0856] In some embodiments, the disease or disorder is Burkitt's
lymphoma, acute myeloblastic leukemia, chronic myeloid leukemia,
non-Hodgkin's lymphoma, Hodgkin's lymphoma, hairy cell leukemia,
Mantle cell lymphoma, small lymphocytic lymphoma, follicular
lymphoma, lymphoplasmacytic lymphoma, extranodal marginal zone
lymphoma, Waldenstrom's macroglobulinemia, prolymphocytic leukemia,
acute lymphoblastic leukemia, myelofibrosis, mucosa-associated
lymphatic tissue (MALT) lymphoma, mediastinal (thymic) large B-cell
lymphoma, lymphomatoid granulomatosis, splenic marginal zone
lymphoma, primary effusion lymphoma, intravascular large B-cell
lymphoma, plasma cell leukemia, extramedullary plasmacytoma,
smouldering myeloma (aka asymptomatic myeloma), monoclonal
gammopathy of undetermined significance (MGUS), or diffuse large B
cell lymphoma.
[0857] In some embodiments, the non-Hodgkin's lymphoma (NHL) is
relapsed NHL, refractory NHL, recucurrent follicular NHL, indolent
NHL (iNHL), or aggressive NHL (aNHL).
[0858] In some embodiments, the diffuse large B cell lymphoma is
activated B-cell like (ABC) diffuse large B cell lymphoma, or
germinal center B cell (GCB) diffuse large B cell lymphoma.
[0859] In some embodiments, the Burkitt's lymphoma is endemic
Burkitt's lymphoma, sporadic Burkitt's lymphoma, or Burkitt's-like
lymphoma
[0860] In some embodiments, the disease or disorder is rheumatoid
arthritis, multiple sclerosis, systemic lupus erythematous, asthma,
allergy (e.g, allergic rhinitis), pancreatitis, psoriasis,
anaphylaxis, glomerulonephritis, inflammatory bowel disease (e.g.,
Crohn's disease and ulcerative colitis), thrombosis, meningitis,
encephalitis, diabetic retinopathy, benign prostatic hypertrophy,
myasthenia gravis, Sjogren's syndrome, osteoarthritis, restenosis,
or atherosclerosis.
[0861] In some embodiments, the disease or disorder is heart
hypertropy, cardiac myocyte dysfunction, acute coronary syndrome,
chronic obstructive pulmonary disease (COPD), chronic bronchitis,
elevated blood pressure, ischemia, ischemia-reperfusion,
vasoconstriction, anemia (e.g., hemolytic anemia, aplastic anemia,
or pure red cell anemia), bacterial infection, viral infection,
graft rejection, kidney disease, anaphylactic shock fibrosis,
skeletal muscle atrophy, skeletal muscle hypertrophy, angiogenesis,
sepsis, graft-versus-host disease, allogeneic or xenogeneic
transplantation, glomerulosclerosis, progressive renal fibrosis,
idiopathic thrombocytopenic purpura (ITP), autoimmune hemolytic
anemia, vasculitis, lupus nephritis, pemphigus, or membranous
nephropathy.
[0862] In some embodiments, disease or disorder is heart
hypertropy, cardiac myocyte dysfunction, chronic obstructive
pulmonary disease (COPD), elevated blood pressure, ischemia,
ischemia-reperfusion, vasoconstriction, anemia (e.g., hemolytic
anemia, aplastic anemia, or pure red cell anemia), bacterial
infection, viral infection, graft rejection, kidney disease,
anaphylactic shock fibrosis, skeletal muscle atrophy, skeletal
muscle hypertrophy, angiogenesis, sepsis, graft rejection,
glomerulosclerosis, progressive renal fibrosis, idiopathic
thrombocytopenic purpura (ITP), autoimmune hemolytic anemia,
vasculitis, systemic lupus erythematosus, lupus nephritis,
pemphigus, or membranous nephropathy.
[0863] In some embodiments, the disease or disorder is Alzheimer's
disease, central nervous system trauma, or stroke.
[0864] In some embodiments, the idiopathic thrombocytopenic purpura
(ITP) is relapsed ITP or refractory ITP.
[0865] In some embodiments, the vasculitis is Behcet's disease,
Cogan's syndrome, giant cell arteritis, polymyalgia rheumatica
(PMR), Takayasu's arteritis, Buerger's disease (thromboangiitis
obliterans), central nervous system vasculitis, Kawasaki disease,
polyarteritis nodosa, Churg-Strauss syndrome, mixed
cryoglobulinemia vasculitis (essential or hepatitis C virus
(HCV)-induced), Henoch-Schonlein purpura (HSP), hypersensitivity
vasculitis, microscopic polyangiitis, Wegener's granulomatosis, or
anti-neutrophil cytoplasm antibody associated (ANCA) systemic
vasculitis (AASV).
[0866] The present invention further provides a compound described
herein, or a pharmaceutically acceptable salt thereof, for use in
any of the methods described herein.
[0867] The present invention further provides use of a compound
described herein, or a pharmaceutically acceptable salt thereof,
for the preparation of a medicament for use in any of the methods
described herein.
[0868] As used herein, the term "contacting" refers to the bringing
together of indicated moieties in an in vitro system or an in vivo
system. For example, "contacting" a PI3K with a compound of the
invention includes the administration of a compound of the present
invention to an individual or patient, such as a human, having a
PI3K, as well as, for example, introducing a compound of the
invention into a sample containing a cellular or purified
preparation containing the PI3K.
[0869] As used herein, the term "individual" or "patient," used
interchangeably, refers to any animal, including mammals,
preferably mice, rats, other rodents, rabbits, dogs, cats, swine,
cattle, sheep, horses, or primates, and most preferably humans.
[0870] As used herein, the phrase "therapeutically effective
amount" refers to the amount of active compound or pharmaceutical
agent that elicits the biological or medicinal response that is
being sought in a tissue, system, animal, individual or human by a
researcher, veterinarian, medical doctor or other clinician.
[0871] As used herein, the term "treating" or "treatment" can refer
to one or more of (1) inhibiting the disease; for example,
inhibiting a disease, condition or disorder in an individual who is
experiencing or displaying the pathology or symptomatology of the
disease, condition or disorder (i.e., arresting further development
of the pathology and/or symptomatology); and (2) ameliorating the
disease; for example, ameliorating a disease, condition or disorder
in an individual who is experiencing or displaying the pathology or
symptomatology of the disease, condition or disorder (i.e.,
reversing the pathology and/or symptomatology) such as decreasing
the severity of disease.
Combination Therapies
[0872] Cancer cell growth and survival can be impacted by multiple
signaling pathways. Thus, it is useful to combine different
enzyme/protein/receptor inhibitors, exhibiting different
preferences in the targets which they modulate the activities of,
to treat such conditions. Targeting more than one signaling pathway
(or more than one biological molecule involved in a given signaling
pathway) may reduce the likelihood of drug-resistance arising in a
cell population, and/or reduce the toxicity of treatment.
[0873] The compounds of the present disclosure can be used in
combination with one or more other enzyme/protein/receptor
inhibitors or one or more therapies for the treatment of diseases,
such as cancer. Examples of diseases and indications treatable with
combination therapies include those as described herein. Examples
of cancers include solid tumors and liquid tumors, such as blood
cancers.
[0874] One or more additional pharmaceutical agents such as, for
example, chemotherapeutics, anti-inflammatory agents, steroids,
immunosuppressants, immune-oncology agents, metabolic enzyme
inhibitors, chemokine receptor inhibitors, and phosphatase
inhibitors, as well as Bcr-Abl, Flt-3, EGFR, HER2, JAK, c-MET,
VEGFR, PDGFR, c-Kit, IGF-1R, RAF and FAK kinase inhibitors such as,
for example, those described in WO 2006/056399. Other agents such
as therapeutic antibodies can be used in combination with the
compounds of the present invention for treatment of PI3K-associated
diseases, disorders or conditions. The one or more additional
pharmaceutical agents can be administered to a patient
simultaneously or sequentially.
[0875] For example, the compounds as disclosed herein can be
combined with one or more inhibitors of the following kinases for
the treatment of cancer and other diseases or disorders described
herein: Akt1, Akt2, Akt3, TGF-.beta.R, PKA, PKG, PKC, CaM-kinase,
phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3,
HER4, INS-R, IGF-1R, IR-R, PDGF.alpha.R, PDGF.beta.R, CSFIR, KIT,
FLK-II, KDR/FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met,
Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR/Flt2, Flt4, EphA1, EphA2,
EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK,
JAK, ABL, ALK and B-Raf. Non-limiting examples of inhibitors that
can be combined with the compounds of the present disclosure for
treatment of cancer and other diseases and disorders described
herein include an FGFR inhibitor (FGFR1, FGFR2, FGFR3 or FGFR4,
e.g., INCB54828, INCB62079 and INCB63904), a JAK inhibitor (JAK1
and/or JAK2, e.g., ruxolitinib, baricitinib or INCB39110), an IDO
inhibitor (e.g., epacadostat, NLG919, or BMS-986205), an LSD1
inhibitor (e.g., INCB59872 and INCB60003), a TDO inhibitor, a
PI3K-delta inhibitor (e.g., INCB50797 and INCB50465), a Pim
inhibitor, a CSF1R inhibitor, a TAM receptor tyrosine kinases
(Tyro-3, Ax1, and Mer), a histone deacetylase inhibitor (HDAC) such
as an HDAC8 inhibitor, an angiogenesis inhibitor, an interleukin
receptor inhibitor, bromo and extra terminal family members
inhibitors (for example, bromodomain inhibitors or BET inhibitors
such as INCB54329 and INCB57643) and an adenosine receptor
antagonist or combinations thereof.
[0876] In some embodiments, the compound or salt described herein
is administered with a PI3K.delta. inhibitor. In some embodiments,
the compound or salt described herein is administered with a JAK
inhibitor. In some embodiments, the compound or salt described
herein is administered with a JAK1 or JAK2 inhibitor (e.g.,
baricitinib or ruxolitinib). In some embodiments, the compound or
salt described herein is administered with a JAK1 inhibitor. In
some embodiments, the compound or salt described herein is
administered with a JAK1 inhibitor, which is selective over
JAK2.
[0877] Example antibodies for use in combination therapy include
but are not limited to Trastuzumab (e.g. anti-HER2), Ranibizumab
(e.g. anti-VEGF-A), Bevacizumab (trade name Avastin, e.g.
anti-VEGF, Panitumumab (e.g. anti-EGFR), Cetuximab (e.g.
anti-EGFR), Rituxan (anti-CD20) and antibodies directed to
c-MET.
[0878] One or more of the following agents may be used in
combination with the compounds of the present invention and are
presented as a non limiting list: a cytostatic agent, cisplatin,
doxorubicin, taxotere, taxol, etoposide, irinotecan, camptostar,
topotecan, paclitaxel, docetaxel, epothilones, tamoxifen,
5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, SCH
66336, R115777, L778,123, BMS 214662, Iressa, Tarceva, antibodies
to EGFR, Gleevec.TM. intron, ara-C, adriamycin, cytoxan,
gemcitabine, Uracil mustard, Chlormethine, Ifosfamide, Melphalan,
Chlorambucil, Pipobroman, Triethylenemelamine,
Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine,
Streptozocin, Dacarbazine, Floxuridine, Cytarabine,
6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate,
oxaliplatin, leucovirin, ELOXATIN.TM. Pentostatine, Vinblastine,
Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin,
Doxorubicin, Epirubicin, Idarubicin, Mithramycin, Deoxycoformycin,
Mitomycin-C, L-Asparaginase, Teniposide 17.alpha.-Ethinylestradiol,
Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone,
Dromostanolone propionate, Testolactone, Megestrolacetate,
Methylprednisolone, Methyltestosterone, Prednisolone,
Triamcinolone, Chlorotrianisene, Hydroxyprogesterone,
Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate,
Leuprolide, Flutamide, Toremifene, goserelin, Cisplatin,
Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane,
Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole,
Capecitabine, Reloxafine, Droloxafine, Hexamethylmelamine, Avastin,
herceptin, Bexxar, Velcade, Zevalin, Trisenox, Xeloda, Vinorelbine,
Porfimer, Erbitux, Liposomal, Thiotepa, Altretamine, Melphalan,
Trastuzumab, Lerozole, Fulvestrant, Exemestane, Fulvestrant,
Ifosfomide, Rituximab, C225, Campath, Clofarabine, cladribine,
aphidicolon, rituxan, sunitinib, dasatinib, tezacitabine, Sml1,
fludarabine, pentostatin, triapine, didox, trimidox, amidox, 3-AP,
and MDL-101,731.
[0879] The compounds of the present disclosure can further be used
in combination with other methods of treating cancers, for example
by chemotherapy, irradiation therapy, tumortargeted therapy,
adjuvant therapy, immunotherapy or surgery. Examples of
immunotherapy include cytokine treatment (e.g., interferons,
GM-CSF, G-CSF, IL-2), CRS-207 immunotherapy, cancer vaccine,
monoclonal antibody, adoptive T cell transfer, Toll receptor
agonists, STING agonists, oncolytic virotherapy and
immunomodulating small molecules, including thalidomide or JAK1/2
inhibitor and the like. The compounds can be administered in
combination with one or more anti-cancer drugs, such as a
chemotherapeutics. Example chemotherapeutics include any of
abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol,
altretamine, anastrozole, arsenic trioxide, asparaginase,
azacitidine, bevacizumab, bexarotene, baricitinib, bleomycin,
bortezombi, bortezomib, busulfan intravenous, busulfan oral,
calusterone, capecitabine, carboplatin, carmustine, cetuximab,
chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide,
cytarabine, dacarbazine, dactinomycin, dalteparin sodium,
dasatinib, daunorubicin, decitabine, denileukin, denileukin
diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolone
propionate, eculizumab, epirubicin, erlotinib, estramustine,
etoposide phosphate, etoposide, exemestane, fentanyl citrate,
filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant,
gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate,
histrelin acetate, ibritumomab tiuxetan, idarubicin, ifosfamide,
imatinib mesylate, interferon alfa 2a, irinotecan, lapatinib
ditosylate, lenalidomide, letrozole, leucovorin, leuprolide
acetate, levamisole, lomustine, meclorethamine, megestrol acetate,
melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C,
mitotane, mitoxantrone, nandrolone phenpropionate, nelarabine,
nofetumomab, oxaliplatin, paclitaxel, pamidronate, panitumumab,
pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin,
pipobroman, plicamycin, procarbazine, quinacrine, rasburicase,
rituximab, ruxolitinib, sorafenib, streptozocin, sunitinib,
sunitinib maleate, tamoxifen, temozolomide, teniposide,
testolactone, thalidomide, thioguanine, thiotepa, topotecan,
toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard,
valrubicin, vinblastine, vincristine, vinorelbine, vorinostat and
zoledronate.
[0880] Additional examples of chemotherapeutics include proteosome
inhibitors (e.g., bortezomib), thalidomide, revlimid, and
DNA-damaging agents such as melphalan, doxorubicin,
cyclophosphamide, vincristine, etoposide, carmustine, and the
like.
[0881] Example steroids include corticosteroids such as
dexamethasone or prednisone.
[0882] Example Bcr-Abl inhibitors include the compounds, and
pharmaceutically acceptable salts thereof, of the genera and
species disclosed in U.S. Pat. No. 5,521,184, WO 04/005281, and
U.S. Ser. No. 60/578,491.
[0883] Example suitable Flt-3 inhibitors include compounds, and
their pharmaceutically acceptable salts, as disclosed in WO
03/037347, WO 03/099771, and WO 04/046120.
[0884] Example suitable RAF inhibitors include compounds, and their
pharmaceutically acceptable salts, as disclosed in WO 00/09495 and
WO 05/028444.
[0885] Example suitable FAK inhibitors include compounds, and their
pharmaceutically acceptable salts, as disclosed in WO 04/080980, WO
04/056786, WO 03/024967, WO 01/064655, WO 00/053595, and WO
01/014402.
[0886] In some embodiments, the compounds of the invention can be
used in combination with one or more other kinase inhibitors
including imatinib, particularly for treating patients resistant to
imatinib or other kinase inhibitors.
[0887] In some embodiments, the compounds of the invention can be
used in combination with a chemotherapeutic in the treatment of
cancer, and may improve the treatment response as compared to the
response to the chemotherapeutic agent alone, without exacerbation
of its toxic effects. In some embodiments, the compounds of the
invention can be used in combination with a chemotherapeutic
provided herein. For example, additional pharmaceutical agents used
in the treatment of multiple myeloma, can include, without
limitation, melphalan, melphalan plus prednisone [MP], doxorubicin,
dexamethasone, and Velcade (bortezomib). Further additional agents
used in the treatment of multiple myeloma include Bcr-Abl, Flt-3,
RAF and FAK kinase inhibitors. In some embodiments, the agent is an
alkylating agent, a proteasome inhibitor, a corticosteroid, or an
immunomodulatory agent. Examples of an alkylating agent include
cyclophosphamide (CY), melphalan (MEL), and bendamustine. In some
embodiments, the proteasome inhibitor is carfilzomib. In some
embodiments, the corticosteroid is dexamethasone (DEX). In some
embodiments, the immunomodulatory agent is lenalidomide (LEN) or
pomalidomide (POM). Additive or synergistic effects are desirable
outcomes of combining a PI3K inhibitor of the present invention
with an additional agent.
[0888] In some embodiments, PI3K.gamma. inhibitors provided herein
can be used in combination with one or more immune checkpoint
inhibitors for the treatment of cancer as described herein. In one
embodiment, the combination with one or more immune checkpoint
inhibitors as described herein can be used for the treatment of
melanoma. Compounds of the present disclosure can be used in
combination with one or more immune checkpoint inhibitors.
Exemplary immune checkpoint inhibitors include inhibitors against
immune checkpoint molecules such as CD20, CD27, CD28, CD40, CD122,
CD96, CD73, CD47, OX40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma,
TAM, arginase, CD137 (also known as 4-1BB), ICOS, A2AR, B7-H3,
B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, PD-1, PD-L1 and PD-L2. In
some embodiments, the immune checkpoint molecule is a stimulatory
checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40,
GITR and CD137. In some embodiments, the immune checkpoint molecule
is an inhibitory checkpoint molecule selected from A2AR, B7-H3,
B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, and VISTA. In some
embodiments, the compounds of the invention provided herein can be
used in combination with one or more agents selected from KIR
inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors,
2B4 inhibitors and TGFR beta inhibitors.
[0889] In some embodiments, the inhibitor of an immune checkpoint
molecule is anti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4
antibody.
[0890] In some embodiments, the inhibitor of an immune checkpoint
molecule is an inhibitor of PD-1, e.g., an anti-PD-1 monoclonal
antibody. In some embodiments, the anti-PD-1 monoclonal antibody is
nivolumab, pembrolizumab (also known as MK-3475), pidilizumab,
SHR-1210, PDR001, or AMP-224. In some embodiments, the anti-PD-1
monoclonal antibody is nivolumab or pembrolizumab. In some
embodiments, the anti-PD1 antibody is pembrolizumab. In some
embodiments, the anti-PD1 antibody is SHR-1210. Other anti-cancer
agent(s) include antibody therapeutics such as 4-1BB (e.g.
urelumab, utomilumab.
[0891] In some embodiments, the inhibitor of an immune checkpoint
molecule is an inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal
antibody. In some embodiments, the anti-PD-L1 monoclonal antibody
is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or
MSB0010718C. In some embodiments, the anti-PD-L1 monoclonal
antibody is MPDL3280A or MEDI4736.
[0892] In some embodiments, the inhibitor of an immune checkpoint
molecule is an inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody.
In some embodiments, the anti-CTLA-4 antibody is ipilimumab or
tremelimumab.
[0893] In some embodiments, the inhibitor of an immune checkpoint
molecule is an inhibitor of LAG3, e.g., an anti-LAG3 antibody. In
some embodiments, the anti-LAG3 antibody is BMS-986016, LAG525, or
INCAGN2385.
[0894] In some embodiments, the inhibitor of an immune checkpoint
molecule is an inhibitor of TIM3, e.g., an anti-TIM3 antibody. In
some embodiments, the anti-TIM3 antibody is INCAGN2390, MBG453, or
TSR-022.
[0895] In some embodiments, the inhibitor of an immune checkpoint
molecule is an inhibitor of GITR, e.g., an anti-GITR antibody. In
some embodiments, the anti-GITR antibody is TRX518, MK-4166,
INCAGN1876, MK-1248, AMG228, BMS-986156, GWN323, or MEDI1873.
[0896] In some embodiments, the inhibitor of an immune checkpoint
molecule is an inhibitor of OX40, e.g., an anti-OX40 antibody or
OX40L fusion protein. In some embodiments, the anti-OX40 antibody
is MEDI0562, MOXR-0916, PF-04518600, GSK3174998, or BMS-986178. In
some embodiments, the OX40L fusion protein is MEDI6383.
[0897] In some embodiments, the inhibitor of an immune checkpoint
molecule is an inhibitor of CD20, e.g., an anti-CD20 antibody. In
some embodiments, the anti-CD20 antibody is obinutuzumab or
rituximab.
[0898] The compounds of the present disclosure can be used in
combination with bispecific antibodies. In some embodiments, one of
the domains of the bispecific antibody targets PD-1, PD-L1, CTLA-4,
GITR, OX40, TIM3, LAG3, CD137, ICOS, CD3 or TGF.beta. receptor.
[0899] In some embodiments, the compounds of the invention can be
used in combination with one or more metabolic enzyme inhibitors.
In some embodiments, the metabolic enzyme inhibitor is an inhibitor
of IDO1, TDO, or arginase. Examples of IDO1 inhibitors include
epacadostat and NGL919.
[0900] In some embodiments, the compounds of the invention can be
used in combination with an inhibitor of JAK or PI3K.delta..
[0901] The agents can be combined with the present compound in a
single or continuous dosage form, or the agents can be administered
simultaneously or sequentially as separate dosage forms.
[0902] The compounds of the present disclosure can be used in
combination with one or more other inhibitors or one or more
therapies for the treatment of infections. Examples of infections
include viral infections, bacterial infections, fungus infections
or parasite infections.
[0903] In some embodiments, a corticosteroid such as dexamethasone
is administered to a patient in combination with the compounds of
the invention where the dexamethasone is administered
intermittently as opposed to continuously.
[0904] The compounds of Formula (I) or any of the formulas as
described herein, a compound as recited in any of the claims and
described herein, or salts thereof can be combined with another
immunogenic agent, such as cancerous cells, purified tumor antigens
(including recombinant proteins, peptides, and carbohydrate
molecules), cells, and cells transfected with genes encoding immune
stimulating cytokines. Non-limiting examples of tumor vaccines that
can be used include peptides of melanoma antigens, such as peptides
of gp100, MAGE antigens, Trp-2, MARTI and/or tyrosinase, or tumor
cells transfected to express the cytokine GM-CSF.
[0905] The compounds of Formula (I) or any of the formulas as
described herein, a compound as recited in any of the claims and
described herein, or salts thereof can be used in combination with
a vaccination protocol for the treatment of cancer. In some
embodiments, the tumor cells are transduced to express GM-CSF. In
some embodiments, tumor vaccines include the proteins from viruses
implicated in human cancers such as Human Papilloma Viruses (HPV),
Hepatitis Viruses (HBV and HCV) and Kaposi's Herpes Sarcoma Virus
(KHSV). In some embodiments, the compounds of the present
disclosure can be used in combination with tumor specific antigen
such as heat shock proteins isolated from tumor tissue itself. In
some embodiments, the compounds of Formula (I) or any of the
formulas as described herein, a compound as recited in any of the
claims and described herein, or salts thereof can be combined with
dendritic cells immunization to activate potent anti-tumor
responses.
[0906] The compounds of the present disclosure can be used in
combination with bispecific macrocyclic peptides that target Fe
alpha or Fe gamma receptor-expressing effectors cells to tumor
cells. The compounds of the present disclosure can also be combined
with macrocyclic peptides that activate host immune
responsiveness.
[0907] In some further embodiments, combinations of the compounds
of the invention with other therapeutic agents can be administered
to a patient prior to, during, and/or after a bone marrow
transplant or stem cell transplant. The compounds of the present
disclosure can be used in combination with bone marrow transplant
for the treatment of a variety of tumors of hematopoietic
origin.
[0908] The compounds of Formula (I) or any of the formulas as
described herein, a compound as recited in any of the claims and
described herein, or salts thereof can be used in combination with
vaccines, to stimulate the immune response to pathogens, toxins,
and self antigens. Examples of pathogens for which this therapeutic
approach may be particularly useful, include pathogens for which
there is currently no effective vaccine, or pathogens for which
conventional vaccines are less than completely effective. These
include, but are not limited to, HIV, Hepatitis (A, B, & C),
Influenza, Herpes, Giardia, Malaria, Leishmania, Staphylococcus
aureus, Pseudomonas Aeruginosa.
[0909] Viruses causing infections treatable by methods of the
present disclosure include, but are not limit to human
papillomavirus, influenza, hepatitis A, B, C or D viruses,
adenovirus, poxvirus, herpes simplex viruses, human
cytomegalovirus, severe acute respiratory syndrome virus, ebola
virus, measles virus, herpes virus (e.g., VZV, HSV-1, HAV-6,
HSV-II, and CMV, Epstein Barr virus), flaviviruses, echovirus,
rhinovirus, coxsackie virus, cornovirus, respiratory syncytial
virus, mumpsvirus, rotavirus, measles virus, rubella virus,
parvovirus, vaccinia virus, HTLV virus, dengue virus,
papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus
and arboviral encephalitis virus.
[0910] Pathogenic bacteria causing infections treatable by methods
of the disclosure include, but are not limited to, chlamydia,
rickettsial bacteria, mycobacteria, staphylococci, streptococci,
pneumonococci, meningococci and conococci, klebsiella, proteus,
serratia, pseudomonas, legionella, diphtheria, salmonella, bacilli,
cholera, tetanus, botulism, anthrax, plague, leptospirosis, and
Lyme's disease bacteria.
[0911] Pathogenic fungi causing infections treatable by methods of
the disclosure include, but are not limited to, Candida (albicans,
krusei, glabrata, tropicalis, etc.), Cryptococcus neoformans,
Aspergillus (fumigatus, niger, etc.), Genus Mucorales (mucor,
absidia, rhizophus), Sporothrix schenkii, Blastomyces dermatitidis,
Paracoccidioides brasiliensis, Coccidioides immitis and Histoplasma
capsulatum. Pathogenic parasites causing infections treatable by
methods of the disclosure include, but are not limited to,
Entamoeba histolytica, Balantidium coli, Naegleriafowleri,
Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis
carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei,
Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi, and
Nippostrongylus brasiliensis.
[0912] Methods for the safe and effective administration of most of
these chemotherapeutic agents are known to those skilled in the
art. In addition, their administration is described in the standard
literature. For example, the administration of many of the
chemotherapeutic agents is described in the "Physicians' Desk
Reference" (PDR, e.g., 1996 edition, Medical Economics Company,
Montvale, N.J.), the disclosure of which is incorporated herein by
reference as if set forth in its entirety.
Pharmaceutical Formulations and Dosage Forms
[0913] When employed as pharmaceuticals, the compounds of the
invention can be administered in the form of pharmaceutical
compositions. These compositions can be prepared in a manner well
known in the pharmaceutical art, and can be administered by a
variety of routes, depending upon whether local or systemic
treatment is desired and upon the area to be treated.
Administration may be topical (including transdermal, epidermal,
ophthalmic and to mucous membranes including intranasal, vaginal
and rectal delivery), pulmonary (e.g., by inhalation or
insufflation of powders or aerosols, including by nebulizer;
intratracheal or intranasal), oral or parenteral. Parenteral
administration includes intravenous, intraarterial, subcutaneous,
intraperitoneal intramuscular or injection or infusion; or
intracranial, e.g., intrathecal or intraventricular,
administration. Parenteral administration can be in the form of a
single bolus dose, or may be, for example, by a continuous
perfusion pump. Pharmaceutical compositions and formulations for
topical administration may include transdermal patches, ointments,
lotions, creams, gels, drops, suppositories, sprays, liquids and
powders. Conventional pharmaceutical carriers, aqueous, powder or
oily bases, thickeners and the like may be necessary or
desirable.
[0914] This invention also includes pharmaceutical compositions
which contain, as the active ingredient, the compound of the
invention or a pharmaceutically acceptable salt thereof, in
combination with one or more pharmaceutically acceptable carriers
(excipients). In some embodiments, the composition is suitable for
topical administration. In making the compositions of the
invention, the active ingredient is typically mixed with an
excipient, diluted by an excipient or enclosed within such a
carrier in the form of, for example, a capsule, sachet, paper, or
other container. When the excipient serves as a diluent, it can be
a solid, semi-solid, or liquid material, which acts as a vehicle,
carrier or medium for the active ingredient. Thus, the compositions
can be in the form of tablets, pills, powders, lozenges, sachets,
cachets, elixirs, suspensions, emulsions, solutions, syrups,
aerosols (as a solid or in a liquid medium), ointments containing,
for example, up to 10% by weight of the active compound, soft and
hard gelatin capsules, suppositories, sterile injectable solutions,
and sterile packaged powders.
[0915] In preparing a formulation, the active compound can be
milled to provide the appropriate particle size prior to combining
with the other ingredients. If the active compound is substantially
insoluble, it can be milled to a particle size of less than 200
mesh. If the active compound is substantially water soluble, the
particle size can be adjusted by milling to provide a substantially
uniform distribution in the formulation, e.g. about 40 mesh.
[0916] The compounds of the invention may be milled using known
milling procedures such as wet milling to obtain a particle size
appropriate for tablet formation and for other formulation types.
Finely divided (nanoparticulate) preparations of the compounds of
the invention can be prepared by processes known in the art, e.g.,
see International App. No. WO 2002/000196.
[0917] Some examples of suitable excipients include lactose,
dextrose, sucrose, sorbitol, mannitol, starches, gum acacia,
calcium phosphate, alginates, tragacanth, gelatin, calcium
silicate, microcrystalline cellulose, polyvinylpyrrolidone,
cellulose, water, syrup, and methyl cellulose.
[0918] The formulations can additionally include: lubricating
agents such as talc, magnesium stearate, and mineral oil; wetting
agents; emulsifying and suspending agents; preserving agents such
as methyl- and propylhydroxy-benzoates; sweetening agents; and
flavoring agents. The compositions of the invention can be
formulated so as to provide quick, sustained or delayed release of
the active ingredient after administration to the patient by
employing procedures known in the art.
[0919] The compositions can be formulated in a unit dosage form,
each dosage containing from about 5 to about 1000 mg (1 g), more
usually about 100 to about 500 mg, of the active ingredient. The
term "unit dosage forms" refers to physically discrete units
suitable as unitary dosages for human subjects and other mammals,
each unit containing a predetermined quantity of active material
calculated to produce the desired therapeutic effect, in
association with a suitable pharmaceutical excipient.
[0920] In some embodiments, the compositions of the invention
contain from about 5 to about 50 mg of the active ingredient. One
having ordinary skill in the art will appreciate that this embodies
compositions containing about 5 to about 10, about 10 to about 15,
about 15 to about 20, about 20 to about 25, about 25 to about 30,
about 30 to about 35, about 35 to about 40, about 40 to about 45,
or about 45 to about 50 mg of the active ingredient.
[0921] In some embodiments, the compositions of the invention
contain from about 50 to about 500 mg of the active ingredient. One
having ordinary skill in the art will appreciate that this embodies
compositions containing about 50 to about 100, about 100 to about
150, about 150 to about 200, about 200 to about 250, about 250 to
about 300, about 350 to about 400, or about 450 to about 500 mg of
the active ingredient.
[0922] In some embodiments, the compositions of the invention
contain from about 500 to about 1000 mg of the active ingredient.
One having ordinary skill in the art will appreciate that this
embodies compositions containing about 500 to about 550, about 550
to about 600, about 600 to about 650, about 650 to about 700, about
700 to about 750, about 750 to about 800, about 800 to about 850,
about 850 to about 900, about 900 to about 950, or about 950 to
about 1000 mg of the active ingredient.
[0923] Similar dosages may be used of the compounds described
herein in the methods and uses of the invention.
[0924] The active compound can be effective over a wide dosage
range and is generally administered in a pharmaceutically effective
amount. It will be understood, however, that the amount of the
compound actually administered will usually be determined by a
physician, according to the relevant circumstances, including the
condition to be treated, the chosen route of administration, the
actual compound administered, the age, weight, and response of the
individual patient, the severity of the patient's symptoms, and the
like.
[0925] For preparing solid compositions such as tablets, the
principal active ingredient is mixed with a pharmaceutical
excipient to form a solid preformulation composition containing a
homogeneous mixture of a compound of the present invention. When
referring to these preformulation compositions as homogeneous, the
active ingredient is typically dispersed evenly throughout the
composition so that the composition can be readily subdivided into
equally effective unit dosage forms such as tablets, pills and
capsules. This solid preformulation is then subdivided into unit
dosage forms of the type described above containing from, for
example, about 0.1 to about 1000 mg of the active ingredient of the
present invention.
[0926] The tablets or pills of the present invention can be coated
or otherwise compounded to provide a dosage form affording the
advantage of prolonged action. For example, the tablet or pill can
comprise an inner dosage and an outer dosage component, the latter
being in the form of an envelope over the former. The two
components can be separated by an enteric layer which serves to
resist disintegration in the stomach and permit the inner component
to pass intact into the duodenum or to be delayed in release. A
variety of materials can be used for such enteric layers or
coatings, such materials including a number of polymeric acids and
mixtures of polymeric acids with such materials as shellac, cetyl
alcohol, and cellulose acetate.
[0927] The liquid forms in which the compounds and compositions of
the present invention can be incorporated for administration orally
or by injection include aqueous solutions, suitably flavored
syrups, aqueous or oil suspensions, and flavored emulsions with
edible oils such as cottonseed oil, sesame oil, coconut oil, or
peanut oil, as well as elixirs and similar pharmaceutical
vehicles.
[0928] Compositions for inhalation or insufflation include
solutions and suspensions in pharmaceutically acceptable, aqueous
or organic solvents, or mixtures thereof, and powders. The liquid
or solid compositions may contain suitable pharmaceutically
acceptable excipients as described supra. In some embodiments, the
compositions are administered by the oral or nasal respiratory
route for local or systemic effect. Compositions can be nebulized
by use of inert gases. Nebulized solutions may be breathed directly
from the nebulizing device or the nebulizing device can be attached
to a face mask, tent, or intermittent positive pressure breathing
machine. Solution, suspension, or powder compositions can be
administered orally or nasally from devices which deliver the
formulation in an appropriate manner.
[0929] Topical formulations can contain one or more conventional
carriers. In some embodiments, ointments can contain water and one
or more hydrophobic carriers selected from, for example, liquid
paraffin, polyoxyethylene alkyl ether, propylene glycol, white
Vaseline, and the like. Carrier compositions of creams can be based
on water in combination with glycerol and one or more other
components, e.g. glycerinemonostearate, PEG-glycerinemonostearate
and cetylstearyl alcohol. Gels can be formulated using isopropyl
alcohol and water, suitably in combination with other components
such as, for example, glycerol, hydroxyethyl cellulose, and the
like. In some embodiments, topical formulations contain at least
about 0.1, at least about 0.25, at least about 0.5, at least about
1, at least about 2, or at least about 5 wt % of the compound of
the invention. The topical formulations can be suitably packaged in
tubes of, for example, 100 g which are optionally associated with
instructions for the treatment of the select indication, e.g.,
psoriasis or other skin condition.
[0930] The amount of compound or composition administered to a
patient will vary depending upon what is being administered, the
purpose of the administration, such as prophylaxis or therapy, the
state of the patient, the manner of administration, and the like.
In therapeutic applications, compositions can be administered to a
patient already suffering from a disease in an amount sufficient to
cure or at least partially arrest the symptoms of the disease and
its complications. Effective doses will depend on the disease
condition being treated as well as by the judgment of the attending
clinician depending upon factors such as the severity of the
disease, the age, weight and general condition of the patient, and
the like.
[0931] The compositions administered to a patient can be in the
form of pharmaceutical compositions described above. These
compositions can be sterilized by conventional sterilization
techniques, or may be sterile filtered. Aqueous solutions can be
packaged for use as is, or lyophilized, the lyophilized preparation
being combined with a sterile aqueous carrier prior to
administration. The pH of the compound preparations typically will
be between 3 and 11, more preferably from 5 to 9 and most
preferably from 7 to 8. It will be understood that use of certain
of the foregoing excipients, carriers, or stabilizers will result
in the formation of pharmaceutical salts.
[0932] The therapeutic dosage of a compound of the present
invention can vary according to, for example, the particular use
for which the treatment is made, the manner of administration of
the compound, the health and condition of the patient, and the
judgment of the prescribing physician. The proportion or
concentration of a compound of the invention in a pharmaceutical
composition can vary depending upon a number of factors including
dosage, chemical characteristics (e.g., hydrophobicity), and the
route of administration. For example, the compounds of the
invention can be provided in an aqueous physiological buffer
solution containing about 0.1 to about 10% w/v of the compound for
parenteral administration. Some typical dose ranges are from about
1 .mu.g/kg to about 1 g/kg of body weight per day. In some
embodiments, the dose range is from about 0.01 mg/kg to about 100
mg/kg of body weight per day. The dosage is likely to depend on
such variables as the type and extent of progression of the disease
or disorder, the overall health status of the particular patient,
the relative biological efficacy of the compound selected,
formulation of the excipient, and its route of administration.
Effective doses can be extrapolated from dose-response curves
derived from in vitro or animal model test systems.
[0933] The compositions of the invention can further include one or
more additional pharmaceutical agents such as a chemotherapeutic,
steroid, anti-inflammatory compound, or immunosuppressant, examples
of which are listed herein.
Labeled Compounds and Assay Methods
[0934] Another aspect of the present invention relates to labeled
compounds of the invention (radio-labeled, fluorescent-labeled,
etc.) that would be useful not only in imaging techniques but also
in assays, both in vitro and in vivo, for localizing and
quantitating PI3K in tissue samples, including human, and for
identifying PI3K ligands by inhibition binding of a labeled
compound. Accordingly, the present invention includes PI3K assays
that contain such labeled compounds.
[0935] The present invention further includes isotopically-labeled
compounds of the invention. An "isotopically" or "radio-labeled"
compound is a compound of the invention where one or more atoms are
replaced or substituted by an atom having an atomic mass or mass
number different from the atomic mass or mass number typically
found in nature (i.e., naturally occurring). Suitable radionuclides
that may be incorporated in compounds of the present invention
include but are not limited to .sup.2H (also written as D for
deuterium), .sup.3H (also written as T for tritium), .sup.11C,
.sup.13C, .sup.14C, .sup.13N, .sup.15N, .sup.15O, .sup.17O,
.sup.18O, .sup.18F, .sup.35S, .sup.36Cl, .sup.82Br, .sup.75Br,
.sup.76Br, .sup.77Br, .sup.123I, .sup.124I, .sup.125I, and
.sup.131I. For example, one or more hydrogen atoms in a compound of
the present disclosure can be replaced by deuterium atoms (e.g.,
one or more hydrogen atoms of a C.sub.1-6 alkyl group of Formula
(I) can be optionally substituted with deuterium atoms, such as
--CD.sub.3 being substituted for --CH.sub.3). The radionuclide that
is incorporated in the instant radio-labeled compounds will depend
on the specific application of that radio-labeled compound. For
example, for in vitro PI3K labeling and competition assays,
compounds that incorporate .sup.3H, .sup.14C, .sup.82Br, .sup.125I,
.sup.131I, .sup.35S or will generally be most useful. For
radio-imaging applications .sup.11C, .sup.18F, .sup.125, .sup.123I,
.sup.124I, .sup.131I, .sup.75Br, .sup.76Br or .sup.77Br will
generally be most useful.
[0936] It is understood that a "radio-labeled" or "labeled
compound" is a compound that has incorporated at least one
radionuclide. In some embodiments the radionuclide is selected from
the group consisting of .sup.3H, .sup.14C, .sup.125I, .sup.35S and
.sup.82Br.
[0937] The present invention can further include synthetic methods
for incorporating radio-isotopes into compounds of the invention.
Synthetic methods for incorporating radio-isotopes into organic
compounds are well known in the art, and an ordinary skill in the
art will readily recognize the methods applicable for the compounds
of invention.
[0938] A labeled compound of the invention can be used in a
screening assay to identify/evaluate compounds. For example, a
newly synthesized or identified compound (i.e., test compound)
which is labeled can be evaluated for its ability to bind a PI3K by
monitoring its concentration variation when contacting with the
PI3K, through tracking of the labeling. For example, a test
compound (labeled) can be evaluated for its ability to reduce
binding of another compound which is known to bind to a PI3K (i.e.,
standard compound). Accordingly, the ability of a test compound to
compete with the standard compound for binding to the PI3K directly
correlates to its binding affinity. Conversely, in some other
screening assays, the standard compound is labeled and test
compounds are unlabeled. Accordingly, the concentration of the
labeled standard compound is monitored in order to evaluate the
competition between the standard compound and the test compound,
and the relative binding affinity of the test compound is thus
ascertained.
Kits
[0939] The present invention also includes pharmaceutical kits
useful, for example, in the treatment or prevention of
PI3K-associated diseases or disorders, such as cancer, which
include one or more containers containing a pharmaceutical
composition comprising a therapeutically effective amount of a
compound of the invention. Such kits can further include, if
desired, one or more of various conventional pharmaceutical kit
components, such as, for example, containers with one or more
pharmaceutically acceptable carriers, additional containers, etc.,
as will be readily apparent to those skilled in the art.
Instructions, either as inserts or as labels, indicating quantities
of the components to be administered, guidelines for
administration, and/or guidelines for mixing the components, can
also be included in the kit.
[0940] The invention will be described in greater detail by way of
specific examples. The following examples are offered for
illustrative purposes, and are not intended to limit the invention
in any manner. Those of skill in the art will readily recognize a
variety of non-critical parameters which can be changed or modified
to yield essentially the same results. The compounds of the
Examples have been found to be PI3K.gamma. inhibitors according to
at least one assay described herein.
EXAMPLES
[0941] Preparatory LC-MS purifications of some of the compounds
prepared were performed on Waters mass directed fractionation
systems. The basic equipment setup, protocols, and control software
for the operation of these systems have been described in detail in
the literature (see e.g. "Two-Pump At Column Dilution Configuration
for Preparative LC-MS", K. Blom, J Combi. Chem., 4, 295 (2002);
"Optimizing Preparative LC-MS Configurations and Methods for
Parallel Synthesis Purification", K. Blom, R. Sparks, J. Doughty,
G. Everlof, T. Haque, A. Combs, J Combi. Chem., 5, 670 (2003); and
"Preparative LC-MS Purification: Improved Compound Specific Method
Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Combi.
Chem., 6, 874-883 (2004)). The compounds separated were typically
subjected to analytical liquid chromatography mass spectrometry
(LCMS) for purity analysis under the following conditions:
Instrument; Agilent 1100 series, LC/MSD, Column: Waters Sunfire.TM.
C.sub.18 5 .mu.m, 2.1.times.50 mm, Buffers: mobile phase A: 0.025%
TFA in water and mobile phase B: acetonitrile; gradient 2% to 80%
of B in 3 minutes with flow rate 2.0 mL/minute.
[0942] Some of the compounds prepared were also separated on a
preparative scale by reverse-phase high performance liquid
chromatography (RP-HPLC) with MS detector or flash chromatography
(silica gel) as indicated in the Examples. Typical preparative
reverse-phase high performance liquid chromatography (RP-HPLC)
column conditions are as follows:
[0943] pH=2 purifications: Waters Sunfire.TM. C.sub.18 5 .mu.m,
19.times.100 mm column, eluting with mobile phase A: 0.1% TFA
(trifluoroacetic acid) in water and mobile phase B: acetonitrile;
the flow rate was 30 mL/minute, the separating gradient was
optimized for each compound using the Compound Specific Method
Optimization protocol as described in the literature (see e.g.
"Preparative LCMS Purification: Improved Compound Specific Method
Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J Comb.
Chem., 6, 874-883 (2004)). Typically, the flow rate used with the
30.times.100 mm column was 60 mL/minute.
[0944] pH=10 purifications: Waters XBridge C.sub.18 5 .mu.m,
19.times.100 mm column, eluting with mobile phase A: 0.15%
NH.sub.4OH in water and mobile phase B: acetonitrile; the flow rate
was 30 mL/minute, the separating gradient was optimized for each
compound using the Compound Specific Method Optimization protocol
as described in the literature (see e.g. "Preparative LCMS
Purification: Improved Compound Specific Method Optimization", K.
Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883
(2004)). Typically, the flow rate used with 30.times.100 mm column
was 60 mL/minute.
[0945] The invention will be described in greater detail by way of
specific examples. The following examples are offered for
illustrative purposes, and are not intended to limit the invention
in any manner. Those of skill in the art will readily recognize a
variety of noncritical parameters which can be changed or modified
to yield essentially the same results.
Example 1.
3-(8-Aminoimidazo[1,2-a]pyridin-3-yl)-N-(trans-4-hydroxycyclohe-
xyl)-4-methylbenzenesulfonamide Trifluoroacetate
##STR00104##
[0946] Step 1.
3-Bromo-N-(trans-4-hydroxycyclohexyl)-4-methylbenzenesulfonamide
##STR00105##
[0948] To a mixture of trans-4-aminocyclohexanol (0.47 g, 4.1
mmol), 4-dimethylaminopyridine (9 mg, 0.07 mmol), and triethylamine
(1.0 mL, 7.4 mmol) in DCM (20 mL) at 0.degree. C. was added
3-bromo-4-methylbenzenesulfonyl chloride (1.0 g, 3.7 mmol)
(Combi-Blocks, WZ-9240) in a single portion. The reaction mixture
was stirred overnight while coming to room temperature. The
reaction was then quenched with sat. NaHCO.sub.3. The organic layer
was removed, and the aqueous layer was extracted with DCM
(2.times.). The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered, and concentrated. Purification via
silica gel chromatography (20-75% EtOAc in DCM (1% MeOH)) afforded
the title compound as a white solid (0.94 g, 73%). LCMS for
C.sub.13H.sub.18BrNO.sub.3SNa (M+Na).sup.+: calculated m/z=370.0,
372.0; found 370.0, 372.0.
Step 2.
N-(trans-4-Hydroxycyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,-
2-dioxaborolan-2-yl)benzenesulfonamide
##STR00106##
[0950] Two microwave vials were each charged with a mixture of
3-bromo-N-(trans-4-hydroxycyclohexyl)-4-methylbenzenesulfonamide
(0.47 g, 1.4 mmol), bis(pinacolato)diboron (0.43 g, 1.7 mmol), KOAc
(0.43 g, 4.4 mmol), and
dichloro[bis(triphenylphosphoranyl)]palladium (38 mg, 0.055 mmol).
THF (25 mL) was added to each vial, and the reaction mixtures were
degassed with N.sub.2 for 5 min. The reaction mixtures were then
heated at 140.degree. C. in a microwave for 20 min. The reaction
mixtures were diluted with EtOAc, combined, and filtered through
Celite. The Celite was then rinsed with EtOAc. The filtrate was
washed with water and then brine, dried over Na.sub.2SO.sub.4,
filtered, and concentrated. Purification via silica gel
chromatography (1-7% MeOH in DCM) afforded the title compound a
white solid (1.3 g, >99%). LCMS for C.sub.19H.sub.31BNO.sub.5S
(M+H).sup.+: calculated m/z=396.2; found 396.2.
Step 3.
3-(8-Aminoimidazo[1,2-a]pyridin-3-yl)-N-(trans-4-hydroxycyclohexyl-
)-4-methylbenzenesulfonamide Trifluoroacetate
[0951] A 1-dram vial was charged with
3-bromoimidazo[1,2-a]pyridin-8-amine (2 mg, 0.009 mmol) (Synthonix,
B0590),
N-(trans-4-hydroxycyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxa-
borolan-2-yl)benzenesulfonamide (3.5 mg, 0.0088 mmol), and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II),
complex with dichloromethane (1 mg, 0.002 mmol). THF (0.12 mL) and
then 1.0 M K.sub.2CO.sub.3 in water (22 .mu.L, 0.022 mmol) were
added. The reaction mixture was degassed with N.sub.2 briefly and
subsequently heated at 80.degree. C. overnight. The reaction
mixture was diluted with MeOH and filtered through Celite.
Purification via preparative HPLC on a C-18 column (pH 2, 12-32%
MeCN/0.1% TFA (aq) over 5 min, 60 mL/min) afforded the title
compound as an off-white solid (1.8 mg, 40%). LCMS for
C.sub.20H.sub.25N.sub.4O.sub.3S (M+H).sup.+: calculated m/z=401.2;
found 401.1.
Example 2.
N-[5-(8-Aminoimidazo[1,2-a]pyridin-3-yl)-2-fluoropyridin-3-yl]e-
thanesulfonamide Bis(Trifluoroacetate)
##STR00107##
[0952] Step 1.
N-(5-bromo-2-fluoropyridin-3-yl)ethanesulfonamide
##STR00108##
[0954] To a solution of 5-bromo-2-fluoropyridin-3-amine (3 g, 20
mmol) in pyridine (10 mL) and DCM (20 mL) at room temperature was
added ethanesulfonyl chloride (2.2 mL, 24 mmol). After stirring for
30 min, the solvent was evaporated. The resulting residue was
diluted with MeOH (4 mL) and partitioned between EtOAc and brine.
The organic layer was separated, and the aq. layer was extracted
with EtOAc. The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered, and concentrated. Purification via
silica gel chromatography afforded the title compound (2 g, 40%).
LCMS for C.sub.7H.sub.9BrFN.sub.2O.sub.2S (M+H).sup.+: calculated
m/z=283.0, 285.0; found 283.0, 284.9.
Step 2.
N-[2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-
-3-yl]ethanesulfonamide
##STR00109##
[0956] A mixture of bis(pinacolato)diboron (0.77 g, 3.0 mmol),
N-(5-bromo-2-fluoropyridin-3-yl)ethanesulfonamide (1.0 g, 0.32
mmol), and KOAc (1.3 g, 13 mmol) in 1,4-dioxane (50 mL,) was
degassed by N.sub.2 for 5 min. Then
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II),
complex with dichloromethane (260 mg, 0.32 mmol) was added, and the
resultant mixture was heated for 1 h at 120.degree. C. The crude
mixture was filtered through Celite to afford the title compound as
a solution in 1,4-dioxane. LCMS for
C.sub.13H.sub.21BFN.sub.2O.sub.4S (M+H).sup.+: calculated
m/z=331.1; found 331.0.
Step 3.
N-[5-(8-Aminoimidazo[1,2-a]pyridin-3-yl)-2-fluoropyridin-3-yl]etha-
nesulfonamide Bis(Trifluoroacetate)
[0957] The title compound was synthesized according to an
experimental procedure analogous to the synthesis of Example 1,
Step 3 substituting a solution of
N-[2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]e-
thanesulfonamide in 1,4-dioxane for
N-(trans-4-hydroxycyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxa-
borolan-2-yl)benzenesulfonamide. LCMS for
C.sub.14H.sub.15FN.sub.5O.sub.2S (M+H).sup.+: calculated m/z=336.1;
found 336.1.
Example 3.
3-(8-Aminoimidazo[1,2-a]pyridin-3-yl)-4-methyl-N-[(3-methyloxet-
an-3-yl)methyl]benzenesulfonamide Trifluoroacetate
##STR00110##
[0958] Step 1.
3-Bromo-4-methyl-N-[(3-methyloxetan-3-yl)methyl]benzenesulfonamide
##STR00111##
[0960] To a solution of 3-bromo-4-methylbenzenesulfonyl chloride
(500.0 mg, 1.855 mmol) (Combi-Blocks, WZ-9240) in THF (10.0 mL) and
pyridine (0.300 mL, 3.71 mmol) was added
1-(3-methyloxetan-3-yl)methanamine (225 mg, 2.22 mmol)
(Combi-Blocks, SS-0093). The resulting mixture was stirred at room
temperature overnight. The reaction mixture was then concentrated
in vacuo. The resulting residue was added to 1.0 N HCl (100 mL) and
extracted with EtOAc (2.times.100 mL). The combined organic layers
were washed with sat. Na.sub.2CO.sub.3 solution (100 mL) and brine,
dried over MgSO.sub.4, filtered, and concentrated. Purification via
on silica gel chromatography (10-80% EtOAc/hexanes) afforded the
title compound (296.0 mg, 48%). LCMS for
C.sub.12H.sub.17BrNO.sub.3S (M+H).sup.+: calculated m/z=334.0,
336.0; found 333.9, 335.9.
Step 2.
4-Methyl-N-[(3-methyloxetan-3-yl)methyl]-3-(4,4,5,5-tetramethyl-1,-
3,2-dioxaborolan-2-yl)benzenesulfonamide
##STR00112##
[0962] To a vial was added
3-bromo-4-methyl-N-[(3-methyloxetan-3-yl)methyl]benzenesulfonamide
(296 mg, 0.886 mmol), KOAc (156 mg, 1.59 mmol),
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II),
complex with dichloromethane (36.2 mg, 0.0443 mmol),
bis(pinicolato)diboron (337 mg, 1.33 mmol), and 1,2-dimethoxyethane
(4.43 mL, 42.6 mmol). The mixture was degassed by bubbling N.sub.2
for 10 minutes. The vial was then sealed, and the reaction mixture
was heated at 90.degree. C. for 2 h. The reaction mixture was then
poured into water and extracted with EtOAc. The organic layer was
washed with brine, dried over MgSO.sub.4, filtered, and
concentrated. Purification via silica gel chromatography (10-40%
EtOAc [5% MeOH]/hexanes) afforded the title compound (96.0 mg,
31%). LCMS for C.sub.18H.sub.29BNO.sub.5S (M+H).sup.+: calculated
m/z=382.2; found 382.2.
Step 3.
3-(8-Aminoimidazo[1,2-a]pyridin-3-yl)-4-methyl-N-[(3-methyloxetan--
3-yl)methyl]benzenesulfonamide Trifluoroacetate
[0963] The title compound was synthesized according to an
experimental procedure analogous to the synthesis of Example 1,
Step 3 substituting
4-methyl-N-[(3-methyloxetan-3-yl)methyl]-3-(4,4,5,5-tetramethyl-1,3,2-dio-
xaborolan-2-yl)benzenesulfonamide for
N-(trans-4-hydroxycyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxa-
borolan-2-yl)benzenesulfonamide. .sup.1H NMR (400 MHz,
d.sub.6-DMSO) .delta. 8.22 (s, 1H), 8.06-7.80 (m, 3H), 7.73 (dd,
J=8.3, 4.7 Hz, 1H), 7.47 (d, J=6.7 Hz, 1H), 7.12 (t, J=7.0 Hz, 1H),
6.89 (d, J=7.4 Hz, 1H), 6.26 (s, 2H), 4.30 (d, J=5.9 Hz, 2H), 4.17
(d, J=5.9 Hz, 2H), 2.97 (d, J=6.5 Hz, 2H), 2.25 (s, 3H), 1.19 (s,
3H). LCMS for C.sub.19H.sub.23N.sub.4O.sub.3S (M+H).sup.+:
calculated m/z=387.1; found 387.1.
Example 4.
3-(8-Amino-6-chloroimidazo[1,2-a]pyridin-3-yl)-N-(trans-4-hydro-
xycyclohexyl)-4-methylbenzenesulfonamide Trifluoroacetate
##STR00113##
[0964] Step 1. 6-Chloroimidazo[1,2-a]pyridin-8-amine
##STR00114##
[0966] To a solution of 5-chloro-2,3-diaminopyridine (1 g, 7 mmol)
in ethanol (50 mL) was slowly added chloroacetaldehyde (3.5 mL, 27
mmol, 50% in H.sub.2O). The reaction mixture was refluxed for 6 h.
Heating was discontinued, and the reaction mixture was stirred
overnight. The reaction mixture was concentrated. Et.sub.2O was
added to the resulting residue, and the solvent was removed in
vacuo. The resulting oil was dissolved in water, and the aqueous
layer was basified by addition of 1 M NaOH (aq). The aqueous layer
was then extracted with DCM (3.times.). The combined organic layers
were dried over MgSO.sub.4, filtered, and concentrated.
Purification via silica gel chromatography (1-10% MeOH in DCM)
afforded the title compound as a light brown solid (0.9 g, 80%).
.sup.1H NMR (600 MHz, d.sub.6-DMSO) .delta. 7.99 (d, J=1.9 Hz, 1H),
7.79 (d, J=1.1 Hz, 1H), 7.45 (d, J=1.1 Hz, 1H), 6.21 (d, J=1.9 Hz,
1H), 6.01 (s, 2H). LCMS for C.sub.7H.sub.7ClN.sub.3 (M+H).sup.+:
calculated m/z=168.0; found 168.1.
Step 2. N-(6-Chloroimidazo[1,2-a]pyridin-8-yl)acetamide
##STR00115##
[0968] To a solution of 6-chloroimidazo[1,2-a]pyridin-8-amine (0.25
g, 1.5 mmol) and 4-dimethylaminopyridine (5 mg, 0.04 mmol) in DCM
(10 mL) at 0.degree. C. was added triethylamine (0.63 mL, 4.5 mmol)
and then acetic anhydride (0.21 mL, 2.2 mmol). After coming to room
temperature, the reaction mixture was stirred overnight. The
reaction mixture was again cooled to 0.degree. C. Additional
portions of 4-dimethylaminopyridine (7 mg, 0.06 mmol),
triethylamine (0.63 mL, 4.5 mmol), and acetic anhydride (0.21 mL,
2.2 mmol) were added. After coming to room temperature, the
reaction mixture was stirred overnight. The reaction mixture was
diluted with DCM and washed with sat. NaHCO.sub.3 (aq), water, and
then brine. The organic layer was dried over Na.sub.2SO.sub.4,
filtered, and concentrated. Purification via silica gel
chromatography (17-100% EtOAc in hexanes, then 1-10% MeOH in EtOAc)
afforded the title compound as a brown solid (0.12 g, 38%). LCMS
for C.sub.9H9ClN.sub.3O (M+H).sup.+: calculated m/z=210.0; found
210.0.
Step 3. N-(3-Bromo-6-chloroimidazo[1,2-a]pyridin-8-yl)acetamide
##STR00116##
[0970] To a solution of N-(6-chloroimidazo[1,2-a]pyridin-8-yl
acetamide (50. mg, 0.24 mmol) in DCM (6 mL) was added
N-bromosuccinimide (43 mg, 0.24 mmol). The reaction mixture was
stirred at room temperature for 30 min. The mixture was then washed
with Na.sub.2CO.sub.3 (10% aq), dried over Na.sub.2SO.sub.4,
filtered, and concentrated. Purification via silica gel
chromatography (1-10% MeOH in DCM) afforded the title compound as a
tan solid (56 mg, 81%). .sup.1H NMR (600 MHz, CDCl.sub.3) .delta.
8.49 (s, 1H), 8.27 (d, J=1.6 Hz, 1H), 7.89 (d, J=1.7 Hz, 1H), 7.51
(s, 1H), 2.30 (s, 3H). LCMS for C.sub.9H.sub.8BrClN.sub.3O
(M+H).sup.+: calculated m/z=288.0, 289.9; found 288.0, 290.0.
Step 4.
3-(8-Amino-6-chloroimidazo[1,2-a]pyridin-3-yl)-N-(trans-4-hydroxyc-
yclohexyl)-4-methylbenzenesulfonamide Trifluoroacetate
[0971] A 1-dram vial was charged with
N-(3-bromo-6-chloroimidazo[1,2-a]pyridin-8-yl)acetamide (10. mg,
0.035 mmol),
N-(trans-4-hydroxycyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,-
2-dioxaborolan-2-yl)benzenesulfonamide (Example 1, Step 2, 17 mg,
0.043 mmol), and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II),
complex with dichloromethane (6 mg, 0.007 mmol). THF (0.50 mL) and
then 1.0 M K.sub.2CO.sub.3 in water (87 .mu.L, 0.087 mmol) were
added. The reaction mixture was degassed with N.sub.2 for 5 min and
subsequently heated at 80.degree. C. overnight. The reaction
mixture was then diluted with MeOH and filtered through a plug of
Na.sub.2SO.sub.4 and Celite, rinsing with MeOH. The filtrate was
concentrated.
[0972] The resulting residue was dissolved in 10:1 EtOH/conc. HCl
(1.0 mL), and the reaction mixture was heated at 80.degree. C. for
2 h. The reaction mixture was diluted with MeOH and filtered via
syringe filter. Purification via preparative HPLC on a C-18 column
(pH 2, 15-35% MeCN/0.1% TFA (aq) over 5 min, 60 mL/min) afforded
the title compound as a white solid (9.5 mg, 50%). LCMS for
C.sub.20H.sub.24ClN.sub.4O.sub.3S (M+H).sup.+: calculated
m/z=435.1; found 435.2.
Example 5.
N-[6-chloro-3-(5-{[(trans-4-hydroxycyclohexyl)amino]sulfonyl}-2-
-methylphenyl)imidazo[12-a]pyridin-8-yl]acetamide
##STR00117##
[0974] The title compound was synthesized according to experimental
procedures analogous to the synthesis of Example 1, Step 3
substituting
N-(3-bromo-6-chloroimidazo[1,2-a]pyridin-8-yl)acetamide for
3-bromoimidazo[1,2-a]pyridin-8-amine. Purification via preparative
HPLC on a C-18 column (pH 10, 26-46% MeCN/0.1% NH.sub.4OH (aq) over
5 min, 60 mL/min) afforded the title compound as a white residue
(3.4 mg). LCMS for C.sub.22H.sub.26ClN.sub.4O.sub.4S (M+H).sup.+:
calculated m/z=477.1; found 477.1.
Example 6.
N-[5-(8-Amino-6-chloroimidazo[1,2-a]pyridin-3-yl)-2-oxo-1,2-dih-
ydropyridin-3-yl]ethanesulfonamide Trifluoroacetate; and
Example 7.
N-[5-(8-Amino-6-chloroimidazo[1,2-a]pyridin-3-yl)-2-ethoxypyrid-
in-3-yl]ethanesulfonamide Bis(Trifluoroacetate)
##STR00118##
[0976] The title compound was synthesized according to experimental
procedures analogous to the synthesis of Example 4, Step 4
substituting a solution of
N-[2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]e-
thanesulfonamide in 1,4-dioxane (Example 2, Step 2) for
N-(trans-4-hydroxycyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxa-
borolan-2-yl)benzenesulfonamide. Purification via preparative HPLC
on a C-18 column (pH 2, 15-41% MeCN/0.1% TFA (aq) over 5 min, 60
mL/min) afforded Example 6 as a white solid (4.7 mg, first to
elute, t.sub.R=3.2 min) and Example 7 as an off-white solid (2.8
mg, second to elute, t.sub.R=5.1 min). Example 6: LCMS for
C.sub.14H.sub.15ClN.sub.5O.sub.3S (M+H).sup.+: calculated
m/z=368.1; found 368.1. Example 7: LCMS for
C.sub.1-6H.sub.19ClN.sub.5O.sub.3S (M+H).sup.+: calculated
m/z=396.1; found 396.1.
Example 8.
3-[8-Amino-6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3--
yl]-N-(trans-4-hydroxycyclohexyl)-4-methylbenzenesulfonamide
Bis(Trifluoroacetate)
##STR00119##
[0978] A 1-dram vial was charged with
N-(3-bromo-6-chloroimidazo[1,2-a]pyridin-8-yl)acetamide (Example 4,
Step 3, 30.7 mg, 0.106 mmol),
N-(trans-4-hydroxycyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxa-
borolan-2-yl)benzenesulfonamide (Example 1, Step 2, 52 mg, 0.13
mmol), and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II),
complex with dichloromethane (18 mg, 0.022 mmol). THF (1.6 mL) and
then 1.0 M K.sub.2CO.sub.3 in water (0.27 mL, 0.27 mmol) were
added. The reaction mixture was degassed with N.sub.2 for 5 min and
subsequently heated at 80.degree. C. for 4 h. An additional portion
of
N-(trans-4-hydroxycyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxa-
borolan-2-yl)benzenesulfonamide (15 mg, 0.038 mmol) was added, and
the reaction mixture was subsequently heated at 80.degree. C. for 3
h. The reaction mixture was diluted with MeOH and filtered through
a plug of Na.sub.2SO.sub.4 and Celite, rinsing with MeOH. The
filtrate was concentrated to afford the crude intermediate.
[0979] To 1-dram vial was added a portion of the crude intermediate
(10 mg),
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
(9.3 mg, 0.045 mmol),
bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)
(1 mg, 0.001 mmol), 1-butanol (0.2 mL), CsF (11 mg, 0.072 mmol),
and water (42 .mu.L). The mixture degassed with N.sub.2 for 5 min.
The vial was capped, and the reaction mixture was heated at
100.degree. C. for 1.5 h. Heating was discontinued, and the
reaction mixture was stirred overnight. The reaction mixture was
diluted with MeOH and filtered through a plug of Na.sub.2SO.sub.4
and Celite, rinsing with MeOH.
[0980] The resulting residue was dissolved in 10:1 EtOH/conc. HCl
(0.61 mL), and the reaction mixture was heated at 80.degree. C. for
1 h. The reaction mixture was diluted with MeOH and filtered via
syringe filter. Purification via preparative HPLC on a C-18 column
(pH 2, 14-34% MeCN/0.1% TFA (aq) over 5 min, 60 mL/min) afforded
the title compound as a white solid (3.6 mg). LCMS for
C.sub.24H.sub.29N.sub.6O.sub.3S (M+H).sup.+: calculated m/z=481.2;
found 481.2.
Example 9 and Example 10
[0981] Examples 9 and 10 were synthesized according to procedures
analogous to the synthesis of Example 8, and the data are listed in
Table 1.
TABLE-US-00001 TABLE 1 ##STR00120## Ex. LCMS No. Name R.sup.8 [M +
H].sup.+ 9 3-(8-Amino-6-pyrimidin-5- ylimidazo[1,2-a]pyridin-
3-yl)-N-(trans-4- hydroxycyclohexyl)-4- methylbenzenesulfonamide
##STR00121## 479.1 10 3-[8-Amino-6-(1-methyl- 1H-pyrazol-5-
yl)imidazo[1,2-a]pyridin- 3-yl]-N-(trans-4- hydroxycyclohexyl)-4-
methylbenzenesulfonamide bis(trifluoroacetate) ##STR00122##
481.2
Example 11.
3-(8-Amino-7-chloroimidazo[1,2-a]pyridin-3-yl)-N-(trans-4-hydroxycyclohex-
yl)-4-methylbenzenesulfonamide Trifluoroacetate
##STR00123##
[0982] Step 1. 7-Chloroimidazo[1,2-a]pyridin-8-amine
##STR00124##
[0984] The title compound was synthesized according to an
experimental procedure analogous to the synthesis of Example 4,
Step 1, substituting 4-chloro-2,3-diaminopyridine (Synthonix,
D0349) for 5-chloro-2,3-diaminopyridine. LCMS for
C.sub.7H.sub.7ClN.sub.3 (M+H).sup.+: calculated m/z=168.0; found
168.0.
Step 2.
N-Acetyl-N-(7-chloroimidazo[1,2-a]pyridin-8-yl)acetamide
##STR00125##
[0986] To a solution of 7-chloroimidazo[1,2-a]pyridin-8-amine (0.50
g, 3.0 mmol) and 4-dimethylaminopyridine (37 mg, 0.30 mmol) in DCM
(20 mL) at 0.degree. C. was added triethylamine (2.5 mL, 18 mmol)
and then acetic anhydride (0.84 mL, 9.0 mmol). After coming to room
temperature, the reaction mixture was stirred overnight at room
temperature. The reaction mixture was then cooled to 0.degree. C.,
and acetyl chloride (0.42 mL, 6.0 mmol) was added dropwise. The
reaction mixture was warmed to room temperature, stirred for 3 h,
and then heated at reflux for 4 h. The reaction mixture was diluted
with DCM and washed successively with sat. NaHCO.sub.3, water, and
brine. The organic layer was dried over Na.sub.2SO.sub.4, filtered,
and concentrated. Purification via silica gel chromatography (1-10%
MeOH in DCM) afforded the title compound as a brown solid (0.68 g,
90%). LCMS for C.sub.11H.sub.11ClN.sub.3O.sub.2(M+H).sup.+:
calculated m/z=252.1; found 252.0.
Step 3.
N-Acetyl-N-(3-bromo-7-chloroimidazo[1,2-a]pyridin-8-yl)acetamide
##STR00126##
[0988] The title compound was synthesized according to an
experimental procedure analogous to the synthesis of Example 4,
Step 3, substituting
N-acetyl-N-(7-chloroimidazo[1,2-a]pyridin-8-yl)acetamide for
N-(6-chloroimidazo[1,2-a]pyridin-8-yl)acetamide. LCMS for
C.sub.11H.sub.9BrClN.sub.3NaO.sub.2 (M+Na).sup.+: calculated
m/z=352.0, 353.9; found 351.8, 353.8.
Step 4.
3-(8-Amino-7-chloroimidazo[1,2-a]pyridin-3-yl)-N-(trans-4-hydroxyc-
yclohexyl)-4-methylbenzenesulfonamide Trifluoroacetate
[0989] The title compound was synthesized according to an
experimental procedure analogous to the synthesis of Example 4,
Step 4, substituting
N-acetyl-N-(3-bromo-7-chloroimidazo[1,2-a]pyridin-8-yl)acetamide
for N-(3-bromo-6-chloroimidazo[1,2-a]pyridin-8-yl)acetamide.
.sup.1H NMR (600 MHz, CD.sub.3OD) .delta. 8.13 (s, 1H), 8.01 (dd,
J=8.2, 2.0 Hz, 1H), 7.96 (d, J=2.0 Hz, 1H), 7.70 (d, J=8.2 Hz, 1H),
7.49 (d, J=7.1 Hz, 1H), 7.35 (d, J=7.1 Hz, 1H), 3.52-3.39 (m, 1H),
3.10-3.01 (m, 1H), 2.29 (s, 3H), 1.86 (apparent d, J=12.0 Hz 2H),
1.77 (apparent d, J=11.9 Hz, 2H), 1.33-1.17 (m, 4H). LCMS for
C.sub.20H.sub.24ClN.sub.4O.sub.3S (M+H).sup.+: calculated
m/z=435.1; found 435.1.
Example 12.
3-[8-Amino-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl]-N-(tra-
ns-4-hydroxycyclohexyl)-4-methylbenzenesulfonamide
##STR00127##
[0990] Step 1.
N-[7-Chloro-3-(5-{[(trans-4-hydroxycyclohexyl)amino]sulfonyl}-2-methylphe-
nyl)imidazo[1,2-a]pyridin-8-yl]acetamide
##STR00128##
[0992] A 1-dram vial was charged with
N-acetyl-N-(3-bromo-7-chloroimidazo[1,2-a]pyridin-8-yl)acetamide
(Example 11, Step 3, 18 mg, 0.054 mmol),
N-(trans-4-hydroxycyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxa-
borolan-2-yl)benzenesulfonamide (Example 1, Step 2, 27 mg, 0.068
mmol), and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II),
complex with dichloromethane (9 mg, 0.01 mmol). THF (0.81 mL) and
then 1.0 M K.sub.2CO.sub.3 in water (0.14 mL, 0.14 mmol) were
added. The reaction mixture was degassed with N.sub.2 for 5 min and
subsequently heated at 80.degree. C. overnight. Additional portions
of
N-(trans-4-hydroxycyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxa-
borolan-2-yl)benzenesulfonamide (28 mg, 0.071 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II),
complex with dichloromethane (9 mg, 0.01 mmol) were added. The
reaction mixture was degassed briefly and subsequently heated at
80.degree. C. for 5 h. The reaction mixture was diluted with DCM
and washed successively with water and brine. The organic layer was
filtered through a plug of Na.sub.2SO.sub.4 and concentrated.
Purification via silica gel chromatography (5-20% MeOH in DCM)
afforded the title compound as a brown solid (27 mg). LCMS for
C.sub.22H.sub.26ClN.sub.4O.sub.4S (M+H).sup.+: calculated
m/z=477.1; found 477.1.
Step 2.
3-[8-Amino-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl]-
-N-(trans-4-hydroxycyclohexyl)-4-methylbenzenesulfonamide
[0993] To 1-dram vial was added
N-[7-chloro-3-(5-{[(trans-4-hydroxycyclohexyl)amino]sulfonyl}-2-methylphe-
nyl)imidazo[1,2-a]pyridin-8-yl]acetamide (8.7 mg, 0.018 mmol),
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
(9 mg, 0.04 mmol),
bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)
(1 mg, 0.001 mmol), 1-butanol (0.2 mL), CsF (11 mg, 0.072 mmol),
and water (36 .mu.L, 2.0 mmol). The solvent degassed with N.sub.2
for 5 min. The vial was capped, and the mixture was heated at
100.degree. C. for 1.5 h. The reaction mixture was diluted with
MeOH and filtered through a plug of Na.sub.2SO.sub.4 and Celite.
The filtrate was concentrated.
[0994] The resulting residue was dissolved in 10:1 EtOH/conc. HCl
(0.53 mL), and the reaction mixture was heated at 80.degree. C. for
8 h. The reaction mixture was diluted with MeCN and filtered via
syringe filter. Purification via preparative HPLC on a C-18 column
(pH 2, 15-35% MeCN/0.1% TFA (aq) over 5 min, 60 mL/min) afforded a
yellow residue (3.3 mg). This residue was partitioned between DCM
and 1 M NaOH (aq). The organic layer was removed, and the aqueous
layer extracted with DCM (2.times.). The organic layers were
filtered through a plug of Na.sub.2SO.sub.4 and concentrated to
afford the title compound as a white residue (0.9 mg). LCMS for
C.sub.24H.sub.29N.sub.6O.sub.3S (M+H).sup.+: calculated m/z=481.2;
found 481.1.
Example 13.
3-(8-Aminoimidazo[1,2-a]pyrazin-3-yl)-N-(trans-4-hydroxycyclohexyl)-4-met-
hylbenzenesulfonamide
##STR00129##
[0996] A microwave vial was charged with
3-bromoimidazo[1,2-a]pyrazin-8-amine (50. mg, 0.23 mmol),
N-(trans-4-hydroxycyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxa-
borolan-2-yl)benzenesulfonamide (Example 1, Step 2, 110 mg, 0.28
mmol), and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II),
complex with dichloromethane (38 mg, 0.047 mmol). THF (3.5 mL) and
then 1.0 M K.sub.2CO.sub.3 in water (0.58 mL, 0.58 mmol) were
added. The reaction mixture was degassed with N.sub.2 for 5 min and
subsequently heated at 80.degree. C. overnight. The reaction
mixture was poured into 50% sat. NaCl (10 mL) and extracted with
DCM (3.times.10 mL). The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered, and concentrated. Purification via
preparative HPLC on a C-18 column (pH 10, 20-33% MeCN/0.1%
NH.sub.4OH (aq) over 5 min, 60 mL/min) afforded a white solid (41
mg, 44%). .sup.1H NMR (600 MHz, d.sub.6-DMSO) .delta. 7.83 (dd,
J=8.1, 2.0 Hz, 1H), 7.76 (d, J=2.0 Hz, 1H), 7.68 (s, 1H), 7.65 (d,
J=8.2 Hz, 1H), 7.63 (br s, 1H), 7.25 (d, J=4.7 Hz, 1H), 7.18 (d,
J=4.7 Hz, 1H), 7.03 (s, 2H), 4.47 (d, J=4.2 Hz, 1H), 3.34-3.24 (m,
1H), 2.98-2.89 (m, 1H), 2.25 (s, 3H), 1.74-1.68 (m, 2H), 1.64-1.57
(m, 2H), 1.22-1.12 (m, 2H), 1.12-1.02 (m, 2H). LCMS for
C.sub.19H.sub.24N.sub.5O.sub.3S (M+H).sup.+: calculated m/z=402.2;
found 402.2.
Example 14.
N-[5-(8-Aminoimidazo[1,2-a]pyrazin-3-yl)-2-fluoropyridin-3-yl]ethanesulfo-
namide Bis(Trifluoroacetate)
##STR00130##
[0998] To a 1-dram vial was added
3-bromoimidazo[1,2-a]pyrazin-8-amine (10. mg, 0.047 mmol)
(Synthonix, A11597), a solution of
N-[2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]e-
thanesulfonamide (Example 2, Step 2, 31 mg, 0.094 mmol) in
1,4-dioxane (1.2 mL, 15 mmol), and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II),
complex with dichloromethane (8 mg, 0.009 mmol). THF (0.70 mL, 8.6
mmol) and then 1.0 M K.sub.2CO.sub.3 in water (0.12 mL, 0.12 mmol)
were added. The reaction mixture was degassed with N.sub.2 for 5
min and subsequently heated at 80.degree. C. overnight. The
reaction mixture was diluted with MeOH and filtered through Celite.
Purification via preparative HPLC on a C-18 column (pH 2, 15-35%
MeCN/0.1% TFA (aq) over 5 min, 60 mL/min) afforded the title
compound as a white solid (9.5 mg, 36%). .sup.1H NMR (600 MHz,
d.sub.6-DMSO) .delta. 10.24 (br s, 1H), 8.86 (br s, 2H), 8.31 (dd,
J=2.0, 1.1 Hz, 1H), 8.14 (dd, J=9.3, 2.2 Hz, 1H), 8.04 (s, 1H),
7.81 (d, J=5.5 Hz, 1H), 7.35 (d, J=5.5 Hz, 1H), 3.28 (q, J=7.3 Hz,
2H), 1.28 (t, J=7.3 Hz, 3H). LCMS for
C.sub.13H.sub.14FN.sub.6O.sub.2S (M+H).sup.+: calculated m/z=337.1;
found 337.1.
Example 15.
3-(8-Aminoimidazo[1,2-a]pyrazin-3-yl)-4-methyl-N-[(3-methyloxetan-3-yl)me-
thyl]benzenesulfonamide Trifluoroacetate
##STR00131##
[1000] The title compound was synthesized according to an
experimental procedure analogous to the synthesis of Example 14,
substituting
4-methyl-N-[(3-methyloxetan-3-yl)methyl]-3-(4,4,5,5-tetramethyl-1,3,2-dio-
xaborolan-2-yl)benzenesulfonamide for a solution of
N-[2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]e-
thanesulfonamide in 1,4-dioxane. LCMS for
C.sub.18H.sub.22N.sub.5O.sub.3S (M+H).sup.+: calculated m/z=388.1;
found 388.1.
Example 16.
3-(8-Amino-6-bromoimidazo[1,2-a]pyrazin-3-yl)-N-(trans-4-hydroxycyclohexy-
l)-4-methylbenzenesulfonamide
##STR00132##
[1001] Step 1. 6,8-Dibromo-3-iodoimidazo[1,2-a]pyrazine
##STR00133##
[1003] To a solution of 6,8-dibromoimidazo[1,2-a]pyrazine (0.50 g,
1.8 mmol) (Combi-Blocks, OR-7964) in DMF (12 mL) was added
N-iodosuccinimide (0.45 g, 2.0 mmol). The reaction mixture was then
heated at 60.degree. C. for 15.5 h. The reaction mixture was
concentrated in vacuo. The resulting solid was taken up into DCM.
The organic layer was washed sequentially with water and sat.
Na.sub.2S.sub.2O.sub.3 (aq). The organic layer was then dried over
Na.sub.2SO.sub.4, filtered, and concentrated to afford the title
compound as a light yellow solid (0.64 g, 88%). LCMS for
C.sub.6H.sub.3Br.sub.2IN.sub.3 (M+H).sup.+: calculated m/z=401.8,
403.8, 405.8; found 401.8, 403.7, 405.6.
Step 2. 6-Bromo-3-iodoimidazo[1,2-a]pyrazin-8-amine
##STR00134##
[1005] A suspension of 6,8-dibromo-3-iodoimidazo[1,2-a]pyrazine
(539 mg, 1.34 mmol) in conc. NH.sub.4OH (aq) (10 mL) was heated at
150.degree. C. for 15 min in a microwave. After cooling to
0.degree. C., the reaction mixture was diluted with cold water and
filtered. The collected solid was then washed with cold water to
afford the title compound as an off-white solid (356 mg, 79%). LCMS
for C.sub.6H.sub.5BrIN.sub.4 (M+H).sup.+: calculated m/z=338.9,
340.9; found 338.8, 340.9.
Step 3.
3-(8-Amino-6-bromoimidazo[1,2-a]pyrazin-3-yl)-N-(trans-4-hydroxycy-
clohexyl)-4-methylbenzenesulfonamide
[1006] A mixture of 6-bromo-3-iodoimidazo[1,2-a]pyrazin-8-amine
(Example 16, Step 2, 0.20 g, 0.59 mmol),
N-(trans-4-hydroxycyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxa-
borolan-2-yl)benzenesulfonamide (Example 1, Step 2, 0.26 g, 0.65
mmol), tetrakis(triphenylphosphine)palladium(0) (45 mg, 0.039
mmol), ethanol (8 mL, 100 mmol), and 2.0 M Na.sub.2CO.sub.3 in
water (0.59 mL, 1.2 mmol) was degassed for 5 min with N.sub.2. The
reaction mixture was then heated at 130.degree. C. for 20 min in a
microwave. The reaction mixture was diluted with DCM and water. The
biphasic mixture was filtered through a plug of Celite. The organic
layer was removed from the filtrate, and the aqueous layer was
extracted with DCM (2.times.). The combined organic layers were
washed with brine, dried over MgSO.sub.4, filtered, and
concentrated. Purification via silica gel chromatography (1-20%
MeOH in DCM) afforded a white solid (0.12 g, 42%). LCMS for
C.sub.19H.sub.22BrN.sub.5O.sub.3S (M+H).sup.+: calculated
m/z=480.1, 482.1; found 480.0, 482.0.
Example 17.
3-[8-Amino-6-(2-methylphenyl)imidazo[1,2-a]pyrazin-3-yl]-N-(trans-4-hydro-
xycyclohexyl)-4-methylbenzenesulfonamide
##STR00135##
[1008] A 1-dram vial was charged with
3-(8-amino-6-bromoimidazo[1,2-a]pyrazin-3-yl)-N-(trans-4-hydroxycyclohexy-
l)-4-methylbenzenesulfonamide (Example 16, 6 mg, 0.01 mmol),
(2-methylphenyl)boronic acid (3 mg, 0.02 mmol), and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II),
complex with dichloromethane (2 mg, 0.002 mmol). THF (0.2 mL) and
then 1.0 M K.sub.2CO.sub.3 in water (31 .mu.L, 0.031 mmol) were
added. The reaction mixture was degassed with N.sub.2 briefly and
then heated at 80.degree. C. for 16 h. Heating was discontinued,
and the reaction mixture was stirred for 2 days. The reaction
mixture was diluted with MeOH and filtered through Celite. The
filtrate was concentrated. Purification via preparative HPLC on a
C-18 column (pH 10, 28-48% MeCN/0.1% NH.sub.4OH (aq) over 5 min, 60
mL/min) afforded the title compound as a white solid (3 mg, 50%).
.sup.1H NMR (600 MHz, d.sub.6-DMSO) .delta. 7.84-7.79 (m, 2H), 7.73
(s, 1H), 7.63 (d, J=8.7 Hz, 1H), 7.34 (d, J=7.2 Hz, 1H), 7.28-7.22
(m, 2H), 7.19 (td, J=7.1, 1.9 Hz, 1H), 7.15 (s, 1H), 7.14 (br s,
2H), 4.43 (d, J=4.2 Hz, 1H), 3.28-3.16 (m, 1H), 2.98-2.85 (m, 1H),
2.34 (s, 3H), 2.29 (s, 3H), 1.70-1.61 (m, 2H), 1.61-1.51 (m, 2H),
1.22-1.07 (m, 2H), 1.07-0.93 (m, 2H). LCMS for
C.sub.26H.sub.30N.sub.5O.sub.3S (M+H).sup.+: calculated m/z=492.2;
found 492.2.
[1009] Examples listed in Table 2 were synthesized according to
procedures analogous to the synthesis of Example 17.
TABLE-US-00002 TABLE 2 ##STR00136## LCMS Ex. Name R.sup.8 [M +
H].sup.+ No. .sup.1H NMR Spectrum 18 3-[8-Amino-6-(4-
methylphenyl)imidazo[1,2- a]pyrazin-3-yl]-N-(trans-4-
hydroxycyclohexyl)-4- methylbenzenesulfonamide ##STR00137## 492.2
19 3-[8-Amino-6-(3- methylphenyl)imidazo[1,2-
a]pyrazin-3-yl]-N-(trans-4- hydroxycyclohexyl)-4-
methylbenzenesulfonamide ##STR00138## 492.2 20 3-[8-Amino-6-(4-
fluorophenyl)imidazo[1,2- a]pyrazin-3-yl]-N-(trans-4-
hydroxycyclohexyl)-4- methylbenzenesulfonamide ##STR00139## 496.1
.sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 7.96-7.89 (m, 2H),
7.88-7.80 (m, 2H), 7.70-7.61 (m, 3H), 7.26-7.15 (m, 3H), 4.48 (d, J
= 4.1 Hz, 1H), 3.39-3.20 (m, 1H), 2.94 (br s, 1H), 2.28 (s, 3H),
1.81-1.54 (m, 4H), 1.28-0.91 (m, 4H). 21 3-[8-Amino-6-(3-
fluorophenyl)imidazo[1,2- a]pyrazin-3-yl]-N-(trans-4-
hydroxycyclohexyl)-4- methylbenzenesulfonamide ##STR00140## 496.1
.sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 7.89-7.80 (m, 2H),
7.78-7.63 (m, 6H), 7.47-7.38 (m, 1H), 7.25 (s, 2H), 7.16 (t, J =
8.3 Hz, 1H), 4.46 (d, J = 3.6 Hz, 1H), 3.40-3.20 (m, 1H), 2.95 (br
s, 1H), 2.28 (s, 3H), 1.65 (m, 4H), 1.27-0.97 (m, 4H). 22
3-[8-Amino-6-(2- fluorophenyl)imidazo[1,2-
a]pyrazin-2-yl]-N-(trans-4- hydroxycyclohexyl)-4-
methylbenzenesulfonamide ##STR00141## 496.1 .sup.1H NMR (400 MHz,
d.sub.6-DMSO) .delta. 8.07 (td, J = 8.0, 1.7 Hz, 1H), 7.87-7.79 (m,
2H), 7.74 (s, 1H), 7.71-7.60 (m, 3H), 7.38 (s, 1H), 7.33-7.17 (m,
4H), 4.46 (d, J = 4.1 Hz, 1H), 3.39-3.19 (m, 1H), 2.92 (br s, 1H),
2.29 (s, 3H), 1.75-1.63 (m, 2H), 1.63-1.51 (m, 2H), 1.25-0.97 (m,
4H). 23 3-[8-Amino-6- phenylimidazo[1,2-a]pyrazin-3-
yl]-N-(trans-4- hydroxycyclohexyl)-4- methylbenzenesulfonamide
##STR00142## 478.2 .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta.
7.90-7.82 (m, 4H), 7.72-7.58 (m, 4H), 7.40 (t, J = 7.3 Hz, 2H),
7.33 (t, J = 7.3 Hz, 1H), 7.20 (s, 2H), 4.47 (d, J = 4.4 Hz, 1H),
3.37-3.21 (m, 1H) 2.95 (s, 1H), 2.29 (s, 3H) 1.65 (m, 4H),
1.26-0.96 (m, 4H). 24 3-[8-Amino-6-(4- cyanophenyl)imidazo[1,2-
a]pyrazin-2-yl]-N-(trans-4- hydroxycyclohexyl)-4-
methylbenzenesulfonamide ##STR00143## 503.2 25
3-(8-Amino-6-pyridin-4- ylimidazo[1,2-a]pyrazin-3-yl)-
N-(trans-4-hydroxycyclohexyl)- 4-methylbenzenesulfonamide
##STR00144## 479.2 26 3-(8-Amino-6-pyridin-3-
ylimidazo[1,2-a]pyrazin-3-yl)- N-(trans-4-hydroxycyclohexyl)-
4-methylbenzenesulfonamide ##STR00145## 479.1 .sup.1H NMR (400 MHz,
d.sub.6-DMSO) .delta. 9.08 (d, J = 2.3 Hz, 1H), 8.52 (dd, J = 4.7,
1.6 Hz, 1H), 8.23 (dt, J = 8.0, 1.9 Hz, 1H), 7.88-7.81 (m, 2H),
7.78 (s, 1H), 7.70 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.42 (dd, J =
8.0, 4.8 Hz, 1H), 7.29 (s, 2H), 4.46 (d, J = 3.1 Hz, 1H), 3.43-3.19
(m, 1H), 2.95 (s, 1H), 2.28 (s, 3H), 1.62 (s, 4H), 1.24-0.95 (m,
4H). 27 3-[8-Amino-6-(2- thienyl)imidazo[1,2-a]pyrazin-
3-yl]-N-(trans-4- hydroxycyclohexyl)-4- methylbenzenesulfonamide
##STR00146## 484.1 28 3-[8-Amino-6-(1-methyl-1H-
pyrazol-5-yl)imidazo[1,2- a]pyrazin-3-yl]-N-(trans-4-
hydroxycyclohexyl)-4- methylbenzenesulfonamide ##STR00147## 482.2
29 3-[8-Amino-6-(1-methyl-1H- pyrazol-4-yl)imidazo[1,2-
a]pyrazin-3-yl]-N-(trans-4- hydroxycyclohexyl)-4-
methylbenzenesulfonamide ##STR00148## 482.2 30
3-[8-Amino-6-(2-fluoro-3- methoxyphenyl)imidazo[1,2-
a]pyrazin-3-yl]-N-(trans-4- hydroxycyclohexyl)-4-
methylbenzenesulfonamide ##STR00149## 526.2 31
3-[8-Amino-3-(5-{[(trans-4- hydroxycyclohexyl)amino] sulfonyl}-2-
methylphenyl)imidazo[1,2- a]pyrazin-6-yl]-4-fluoro-N-
methylbenzamide ##STR00150## 553.2 32 3-{8-Amino-6-[2-fluoro-4-
(hydroxymethyl)phenyl] imidazo[1,2-a]pyrazin-3-yl}-N-
(trans-4-hydroxycyclohexyl)-4- methylbenzenesulfonamide
##STR00151## 526.2 33 3-{8-Amino-6-[3- (methylsulfonyl)phenyl]
imidazo[1,2-a]pyrazin-3-yl}-N- (trans-4-hydroxycyclohexyl)-4-
methylbenzenesulfonamide ##STR00152## 526.2 34
3-[8-Amino-6-(2-fluoro-6- methoxyphenyl)imidazo[1,2-
a]pyrazin-3-yl]-N-(trans-4- hydroxycyclohexyl)-4-
methylbenzenesulfonamide ##STR00153## 556.2 35
3-[8-Amino-6-(2-methylthiazol- 5-yl)imidazo[1,2-a]pyrazin-3-
yl]-N-(trans-4- hydroxycyclohexyl)-4- methylbenzenesulfonamide
##STR00154## 499.2 .sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 7.99
(s, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.79 (s, 1H) 7.70-7.59 (m, 3H),
7.29 (s, 2H), 4.68-4.21 (m, 1H), 3.05-2.83 (m, 1H), 2.62 (s, 3H),
2.25 (s, 3H), 1.85-1.53 (m, 4H), 1.33-0.93 (m, 4H). 75
3-[8-amino-6-(3- methylisoxazol-5- yl)imidazo[1,2-a]pyrazin-3-yl]-
N-(trans-4-hydroxycyclohexyl)- 4-methylbenzenesulfonamide
##STR00155## 483.2 .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. 7.86
(dd, J = 8.1, 1.9 Hz, 1H), 7.81 (d, J = 1.7 Hz, 1H), 7.75 (s, 1H),
7.66 (d, J = 8.1 Hz, 1H), 7.63 (s, 1H), 7.40 (s, 2H), 6.65 (s, 1H),
4.50-4.36 (m, 1H), 3.40-3.32 (m, 1H), 3.02-2.89 (m, 1H), 2.26 (s,
3H), 2.25 (s, 3H), 1.75-1.66 (m, 2H), 1.66-1.57 (m, 2H), 1.28-1.12
(m, 2H), 1.12-1.00 (m, 2H). 76 3-{8-amino-6-[1-(2,2,2-
trifluoroethyl)-1H-pyrazol-4- yl]imidazo[1,2-a]pyrazin-3-yl}-
N-(trans-4-hydroxycyclohexyl)- 4-methylbenzenesulfonamide
##STR00156## 550.4 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.16
(s, 1H), 7.93 (s, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.77 (s, 1H), 7.64
(d, J = 8.1 Hz, 1H), 7.61 (s, 1H), 7.52 (s, 1H), 7.11 (s, 2H), 5.13
(q, J = 9.0 Hz, 2H), 4.55-4.35 (m, 1H), 3.03-2.83 (m, 1H), 2.24 (s,
3H), 1.80-1.53 (m, 4H), 1.28-0.97 (m, 4H). 77 3-[8-amino-6-(3,5-
dimethylisoxazol-4- yl)imidazo[1,2-a]pyrazin-3-yl]-
N-(trans-4-hydroxycyclohexyl)- 4-methylbenzenesulfonamide
##STR00157## 497.2 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
7.84-7.78 (m, 2H), 7.71 (s, 1H), 7.66-7.56 (m, 2H), 7.27 (s, 1H),
7.19 (br s, 2H), 4.45 (d, J = 4.2 Hz, 1H), 3.28-3.20 (m, 1H),
3.01-2.78 (m, 1H), 2.46 (s, 3H), 2.28 (d, J = 12.4 Hz, 6H),
1.74-1.63 (m, 2H), 1.62-1.49 (m, 2H), 1.21-0.95 (m, 4H). 78
3-{8-amino-6-[1-(1-cyano-1- methylethyl)-1H-pyrazol-4-
yl]imidazo[1,2-a]pyrazin-3-yl}- N-(trans-4-hydroxycyclohexyl)-
4-methylbenzenesulfonamide ##STR00158## 535.2 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.32 (s, 1H), 7.99 (s, 1H), 7.85 (d, J = 8.0
Hz, 1H), 7.77 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.61 (s, 1H), 7.55
(s, 1H), 7.13 (s, 2H), 4.47 (br s, 1H), 3.28-3.22 (m, 1 H),
3.03-2.84 (m, 1H), 2.24 (s, 3H), 1.96 (s, 6H), 1.73-1.57 (m, 4H),
1.12 (dq, J = 35.0, 11.7, 9.9 Hz, 4H). 79
4-[8-Amino-3-(5-{[(trans-4- hydroxycyclohexyl)amino] sulfonyl}-2-
methylphenyl)imidazo[1,2- a]pyrazin-6-yl]-3-fluoro-N,N-
dimethylbenzamide trifluoroacetate ##STR00159## 567.2 80
3-{8-Amino-6-[1-methyl-3- (trifluoromethyl)-1H-pyrazol-5-
yl]imidazo[1,2-a]pyrazin-3-yl}- N-(trans-4-hydroxycyclohexyl)-
4-methylbenzenesulfonamide ##STR00160## 550.2 81
3-[8-Amino-6-(3-fluoropyridin- 4-yl)imidazo[1,2-a]pyrazin-3-
yl]-N-(trans-4- hydroxycyclohexyl)-4- methylbenzenesulfonamide
##STR00161## 497.1 82 3-(8-Amino-6-(2-fluoro-4-(1-
hydroxyethyl)phenyl)imidazo [1,2-a]pyrazin-3-yl)-N-(trans-4-
hydroxycyclohexyl)-4- methylbenzenesulfonamide ##STR00162##
540.1
Example 36.
3-[6-(2-Fluorophenyl)-8-(methylamino)imidazo[1,2-a]pyrazin-3-yl]-N-(trans-
-4-hydroxycyclohexyl)-4-methylbenzenesulfonamide
Trifluoroacetate
##STR00163##
[1010] Step 1.
6-Bromo-3-iodo-N-methylimidazo[1,2-a]pyrazin-8-amine
##STR00164##
[1012] The title compound was synthesized according to an
experimental procedure analogous to the synthesis of Example 16,
Step 2 substituting methylamine (40% w/w in water) for conc.
NH.sub.4OH (aq). LCMS for C.sub.7H.sub.7BrIN.sub.4 (M+H).sup.+:
calculated m/z=352.9, 354.9; found 352.9, 354.9.
Step 2.
3-[6-(2-Fluorophenyl)-8-(methylamino)imidazo[1,2-a]pyrazin-3-yl]-N-
-(trans-4-hydroxycyclohexyl)-4-methylbenzenesulfonamide
Trifluoroacetate
[1013] A mixture of
6-bromo-3-iodo-N-methylimidazo[1,2-a]pyrazin-8-amine (7.6 mg, 0.022
mmol),
N-(trans-4-hydroxycyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxa-
borolan-2-yl)benzenesulfonamide (Example 1, Step 2, 10 mg, 0.02
mmol), tetrakis(triphenylphosphine)palladium(0) (2 mg, 0.002 mmol),
ethanol (0.5 mL), and 2.0 M Na.sub.2CO.sub.3 in water (22 .mu.L,
0.043 mmol) was degassed for 5 min with N.sub.2. The reaction
mixture was then heated in a microwave reactor at 130.degree. C.
for 30 min. The reaction mixture was diluted with MeOH and filtered
through a plug of Celite. The filtrate was concentrated to afford
the crude intermediate.
[1014] A 1-dram vial was charged with the crude intermediate,
(2-fluorophenyl)boronic acid (9 mg, 0.06 mmol), and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II),
complex with dichloromethane (4 mg, 0.004 mmol). THF (0.4 mL) and
1.0 M K.sub.2CO.sub.3 in water (56 .mu.L, 0.056 mmol) were added.
The reaction mixture was degassed with N.sub.2 briefly and then
heated at 80.degree. C. overnight. The reaction mixture was diluted
with MeOH and filtered through a plug of Na.sub.2SO.sub.4 and
Celite. Purification via preparative HPLC on a C-18 column (pH 10,
36-56% MeCN/0.1% NH.sub.4OH (aq) over 5 min, 60 mL/min) and then
subsequent purification via preparative HPLC on a C-18 column (pH
2, 31-42% MeCN/0.1% TFA (aq) over 5 min, 60 mL/min) afforded the
title compound as a white solid (4.2 mg, 30%). .sup.1H NMR (400
MHz, d.sub.6-DMSO) .delta. 8.20 (t, J=7.3 Hz, 1H), 7.93-7.83 (br m,
2H), 7.82 (s, 1H), 7.73 (s, 1H), 7.70-7.62 (m, 2H), 7.60 (s, 1H),
7.44-7.36 (m, 1H), 7.32 (t, J=7.5 Hz, 1H), 7.23 (dd, J=12.0, 8.2
Hz, 1H), 3.34-3.20 (m, 1H), 3.08 (d, J=2.2 Hz, 3H), 3.00-2.87 (m,
1H), 1.68 (apparent d, J=10.8 Hz, 2H), 1.59 (apparent d, J=11.6 Hz,
2H), 1.31-0.93 (m, 4H). LCMS for C.sub.26H.sub.29FN.sub.5O.sub.3S
(M+H).sup.+: calculated m/z=510.2; found 510.1.
Example 37.
3-(8-Amino-6-methylimidazo[1,2-a]pyrazin-3-yl)-N-(trans-4-hydroxycyclohex-
yl)-4-methylbenzenesulfonamide
##STR00165##
[1016] The title compound was synthesized according to experimental
procedures analogous to the synthesis of Example 16, substituting
8-bromo-6-methylimidazo[1,2-a]pyrazine (Frontier, B12886) for
6,8-dibromoimidazo[1,2-a]pyrazine. .sup.1H NMR (600 MHz,
d.sub.6-DMSO) .delta. 7.83 (dd, J=8.0, 2.0 Hz, 1H), 7.74 (d, J=2.0
Hz, 1H), 7.64 (d, J=8.1 Hz, 2H), 7.60 (s, 1H), 7.00 (d, J=1.0 Hz,
1H), 6.98 (br s, 2H), 4.47 (d, J=4.2 Hz, 1H), 3.36-3.22 (m, 1H),
3.00-2.87 (m, 1H), 2.23 (s, 3H), 2.15 (d, J=0.8 Hz, 3H), 1.75-1.68
(m, 2H), 1.65-1.57 (m, 2H), 1.22-1.13 (m, 2H), 1.13-1.04 (m, 2H).
LCMS for C.sub.20H.sub.26N.sub.5O.sub.3S (M+H).sup.+: calculated
m/z=416.2; found 416.2.
Example 38.
3-(8-Amino-6-ethylimidazo[1,2-a]pyrazin-3-yl)-N-(trans-4-hydroxycyclohexy-
l)-4-methylbenzenesulfonamide
##STR00166##
[1017] Step 1.
3-(8-Amino-6-vinylimidazo[1,2-a]pyrazin-3-yl)-N-(trans-4-hydroxycyclohexy-
l)-4-methylbenzenesulfonamide
##STR00167##
[1019] A microwave vial was charged with
3-(8-amino-6-bromoimidazo[1,2-a]pyrazin-3-yl)-N-(trans-4-hydroxycyclohexy-
l)-4-methylbenzenesulfonamide (Example 16, 21 mg, 0.044 mmol),
potassium vinyltrifluoroborate (17 mg, 0.12 mmol), and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II),
complex with dichloromethane (6 mg, 0.007 mmol). THF (0.57 mL) and
1.0 M K.sub.2CO.sub.3 in water (0.12 mL, 0.12 mmol) were added. The
reaction mixture was degassed with N.sub.2 for 5 min and
subsequently heated to 80.degree. C. for 4 h. The reaction mixture
was diluted with MeOH and filtered through a plug of
Na.sub.2SO.sub.4 and Celite. The filtrate was concentrated.
Purification via silica gel chromatography (1-10% MeOH in DCM)
afforded the title compound as a light brown solid (17 mg, 91%).
LCMS for C.sub.21H.sub.26N.sub.5O.sub.3S (M+H).sup.+: calculated
m/z=428.2; found 428.3.
Step 2.
3-(8-Amino-6-ethylimidazo[1,2-a]pyrazin-3-yl)-N-(trans-4-hydroxycy-
clohexyl)-4-methylbenzenesulfonamide
[1020] To a solution of
3-(8-amino-6-vinylimidazo[1,2-a]pyrazin-3-yl)-N-(trans-4-hydroxycyclohexy-
l)-4-methylbenzenesulfonamide (8 mg, 0.02 mmol) in ethanol (4 mL)
under N.sub.2 was added wet 10% Pd/C (8 mg, .about.50% H.sub.2O)
[Sigma-Aldrich, 330108]. The reaction mixture was then placed under
an atm of H.sub.2 and stirred for 1 h. The reaction mixture was
filtered through Celite, the Celite plug was rinsed with MeOH, and
the filtrate was concentrated. Purification via preparative HPLC on
a C-18 column (pH 10, 23-40% MeCN/0.1% NH.sub.4OH (aq) over 5 min,
60 mL/min) afforded the title compound as a white solid (5 mg,
60%). .sup.1H NMR (600 MHz, d.sub.6-DMSO) .delta. 7.83 (dd, J=8.0,
2.0 Hz, 1H), 7.75 (d, J=2.0 Hz, 1H), 7.64 (d, J=8.1 Hz, 1H), 7.61
(s, 1H), 6.98 (s, 2H), 6.97 (s, 1H), 4.47 (s, 1H), 3.38-3.24 (m,
1H), 2.99-2.87 (m, 1H), 2.45 (q, J=7.4 Hz, 2H), 2.23 (s, 3H),
1.75-1.66 (m, 2H), 1.65-1.57 (m, 2H), 1.23-1.03 (m, 7H). LCMS for
C.sub.21H.sub.28N.sub.5O.sub.3S (M+H).sup.+: calculated m/z=430.2;
found 430.2.
Example 39.
3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(trans-4-hydroxycyclohexyl-
)-4-methylbenzenesulfonamide
##STR00168##
[1022] The title compound was synthesized according to experimental
procedures analogous to the synthesis of Example 13, substituting
7-bromoimidazo[2,1-f][1,2,4]triazin-4-amine (Synthonix, A8092) for
3-bromoimidazo[1,2-a]pyrazin-8-amine. .sup.1H NMR (600 MHz,
d.sub.6-DMSO) .delta. 8.28 (apparent d, J=48.1 Hz, 2H), 8.06 (s,
1H), 7.91 (d, J=2.0 Hz, 1H), 7.79 (s, 1H), 7.78 (dd, J=8.0, 2.0 Hz,
1H), 7.59 (d, J=8.2 Hz, 1H), 4.47 (s, 1H), 3.39-3.23 (m, 1H),
3.01-2.85 (m, 1H), 2.33 (s, 3H), 1.75-1.67 (m, 2H), 1.67-1.59 (m,
2H), 1.22-1.12 (m, 2H), 1.12-1.02 (m, 2H). LCMS for
C.sub.18H.sub.23N.sub.6O.sub.3S (M+H).sup.+: calculated m/z=403.2;
found 403.2.
Example 40.
6-(2-Fluorophenyl)-3-[2-methyl-5-(methylsulfonyl)phenyl]imidazo[1,2-a]pyr-
azin-8-amine Trifluoroacetate
##STR00169##
[1023] Step 1.
4,4,5,5-Tetramethyl-2-[2-methyl-5-(methylsulfonyl)phenyl]-1,3,2-dioxaboro-
lane
##STR00170##
[1025] The title compound was synthesized according to an
experimental procedure analogous to the synthesis of Example 1,
Step 2 substituting 2-bromo-1-methyl-4-(methylsulfonyl)benzene
(Combi-Blocks, OT-1007) for
3-bromo-N-(trans-4-hydroxycyclohexyl)-4-methylbenzenesulfonamide.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.31 (d, J=2.0 Hz, 1H),
7.86 (dd, J=8.1, 2.2 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 3.04 (s, 3H),
2.62 (s, 3H), 1.35 (s, 12H). LCMS for C.sub.14H.sub.22BO.sub.4S
(M+H).sup.+: calculated m/z=297.1; found 297.1.
Step 2.
6-(2-Fluorophenyl)-3-[2-methyl-5-(methylsulfonyl)phenyl]imidazo[1,-
2-a]pyrazin-8-amine trifluoroacetate
[1026] A mixture of 6-bromo-3-iodoimidazo[1,2-a]pyrazin-8-amine
(Example 16, Step 2, 10. mg, 0.030 mmol),
4,4,5,5-tetramethyl-2-[2-methyl-5-(methylsulfonyl)phenyl]-1,3,2-dioxaboro-
lane (10. mg, 0.035 mmol), tetrakis(triphenylphosphine)palladium(0)
(2 mg, 0.002 mmol), ethanol (0.52 mL), and 2.0 M Na.sub.2CO.sub.3
in water (30 .mu.L, 0.059 mmol) was degassed for 5 min with
N.sub.2. The reaction mixture was then heated in a microwave
reactor at 130.degree. C. for 30 min. The reaction mixture was
diluted with MeOH and filtered through a plug of Na.sub.2SO.sub.4
and Celite. The filtrate was concentrated to afford the crude
intermediate.
[1027] A 1-dram vial was charged with the crude intermediate,
(2-fluorophenyl)boronic acid (12 mg, 0.090 mmol), and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II),
complex with dichloromethane (5 mg, 0.006 mmol). THF (0.5 mL) and
then 1.0 M K.sub.2CO.sub.3 in water (75 L, 0.075 mmol) were added.
The reaction mixture was degassed with N.sub.2 for 15 min and then
heated at 80.degree. C. for 16 h. Heating was discontinued, and the
reaction mixture was stirred for 3 days. The reaction mixture was
diluted with MeOH and filtered through a plug of Na.sub.2SO.sub.4
and Celite. Purification via preparative HPLC on a C-18 column (pH
10, 29-52% MeCN/0.1% NH.sub.4OH (aq) over 5 min, 60 mL/min) and
then subsequent purification via preparative HPLC on a C-18 column
(pH 2, 24-39% MeCN/0.1% TFA (aq) over 5 min, 60 mL/min) afforded
the title compound as a white solid (3.3 mg, 22%). .sup.1H NMR (400
MHz, d.sub.6-DMSO) .delta. 8.06-7.91 (m, 3H), 7.81 (s, 1H), 7.75
(d, J=8.0 Hz, 1H), 7.65 (s, 1H), 7.45-7.37 (m, 1H), 7.35-7.20 (m,
2H), 3.26 (s, 3H), 2.31 (s, 3H). LCMS for
C.sub.20H.sub.18FN.sub.4O.sub.2S (M+H).sup.+: calculated m/z=397.1;
found 397.2.
[1028] Examples listed in Table 3 were synthesized according to
procedures analogous to the synthesis of Example 1, Steps 1 and 2,
and Example 13.
TABLE-US-00003 TABLE 3 ##STR00171## LCMS Ex. Name R = [M + H].sup.+
No. .sup.1H NMR Spectrum 41 5-(8-Aminoimidazo[1,2-a]pymzin-3- 4-Me
402.2 yl)-N-(trans-4-hydroxycyclohexyl)- 2-methylbenzenesulfonamide
.sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.02 (d, J = 1.7 Hz,
1H), 7.83-7.73 (m, 3H), 7.68 (d, J = 4.7 Hz, 1H), 7.56 (d, J = 8.0
Hz, 1H), 7.30 (d, J = 4.7 Hz, 1H), 7.01 (s, 2H), 4.45 (d, J = 4.3
Hz, 1H), 3.28-3.19 (m, 1H), 3.04-2.86 (m, 1H), 2.63 (s, 3H),
1.82-1.53 (m, 4H), 1.38-0.94 (m, 4H) 42
3-(8-Aminoimidazo[1,2-a]pymzin-3-yl)- 2-F 406.1
4-fluoro-N-(trans-4- hydroxycyclohexyl)benzenesulfonamide .sup.1H
NMR (400 MHz, d.sub.6-DMSO) .delta. 8.05-7.99 (m, 1H), 7.99-7.91
(m, 1H), 7.78 (s, 1H), 7.74 (s, 1H), 7.70-7.61 (m, 1H), 7.53-7.44
(m, 1H), 7.30 (d, J = 4.7 Hz, 1H), 7.05 (s, 2H), 4.46 (d, J = 4.2
Hz, 1H), 3.38-3.19 (m, 1H), 3.05-2.88 (m, 1H), 1.81-1.51 (m, 4H),
1.28-0.95 (m, 4H) 43 5-(8-Aminoimidazo[1,2-a]pymzin-3- 4-OMe 418.1
yl)-N-(trans-4-hydroxycyclohexyl)- 2-methoxybenzenesulfonamide
.sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 7.90 (d, J = 2.2 Hz,
1H), 7.88-7.82 (m, 1H), 7.71 (s, 1H), 7.62 (d, J = 4.7 Hz, 1H),
7.38 (d, J = 8.6 Hz, 1H), 7.34 (br s, 1H), 7.28 (d, J = 4.7 Hz,
1H), 6.97 (s, 2H), 4.45 (d, J = 4.1 Hz, 1H), 3.96 (s, 3H),
3.29-3.20 (m, 1H), 3.09-2.94 (m, 1H), 1.78-1.51 (m, 4H), 1.34-0.96
(m, 4H) 44 3-(8-Aminoimidazo[1,2-a]pymzin-3- 3-Me 402.2
yl)-N-(trans-4-hydroxycyclohexyl)- 5-methylbenzenesulfonamide
.sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 7.82 (s, 1H), 7.79 (s,
1H), 7.77- 7.71 (m, 2H), 7.71-7.64 (m, 2H), 7.32 (d, J = 4.7 Hz,
1H), 7.01 (s, 2H), 4.45 (d, J = 4.3 Hz, 1H), 3.28-3.20 (m, 1H),
3.05-2.84 (m, 1H), 2.48 (s, 3H), 1.83-1.47 (m, 4H), 1.33-0.95 (m,
4H) 45 5-(8-Aminoimidazo[1,2-a]pyrazin- 4-F 406.1
3-yl)-2-fluoro-N-(trans-4- hydroxycyclohexyl)benzenesulfonamide
.sup.1H NMR (400 MHz, d.sub.6-DMSO) .delta. 8.03 (s, 1H), 7.99-7.90
(m, 2H), 7.79 (s, 1H), 7.68 (d, J = 4.7 Hz, 1H), 7.66-7.56 (m, 1H),
7.30 (d, J = 4.7 Hz, 1H), 7.01 (s, 2H), 4.47 (d, J = 4.2 Hz, H),
3.29- 3.20 (m, 1H), 3.16-3.01 (m, 1H), 1.82-1.54 (m, 4H), 1.40-1.18
(m, 2H), 1.18-0.96 (m, 2H) 46 5-(8-Aminoimidazo[1,2-a]pyrazin-3-
4-C1 422.1 yl)-2-chloro-N-(trans-4-
hydroxycyclohexyl)benzenesulfonamide .sup.1H NMR (400 MHz,
d.sub.6-DMSO) .delta. 8.15 (d, J = 2.1 Hz, 1H), 7.94 (s, 1H), 7.89
(dd, J = 8.3, 2.1 Hz, 1H), 7.85 (s, 1H), 7.79 (d, J = 8.3 Hz, 1H),
7.73 (d, J = 4.7 Hz, 1H), 7.32 (d, J = 4.7 Hz, 1H), 7.03 (s, 2H),
4.46 (d, J = 4.0 Hz, 1H), 3.33-3.21 (m, 1H), 3.14-2.96 (m, 1H),
1.84-1.53 (m, 4H), 1.42-0.98 (m, 4H) 83
5-(8-aminoimidazo[1,2-a]pyrazin-3- 2-Me, 432.1
yl)-N-(trans-4-hydroxycyclohexyl)- 4-OMe
2-methoxy-4-methylbenzenesulfonamide .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.62 (s, 1H), 7.59 (s, 1H), 7.36- 7.18 (m,
3H), 7.13 (d, J = 4.6 Hz, 1H), 6.96 (s, 2H), 4.45 (d, J = 4.2 Hz,
1H), 3.96 (s, 3H), 3.07-2.87 (m, 1H), 2.19 (s, 3H), 1.78- 1.65 (m,
2H), 1.65-1.48 (m, 2H), 1.33-1.15 (m, 2H), 1.15-0.93 (m, 2H).
[1029] Compounds in the following tables were prepared by Method A
(default method) or Method B as indicated (See footnote or separate
column). Method A: Sulfonamide formation precedes Suzuki coupling
(e.g., Example 1, Steps 1 and 2; Example 13); Method B: Sulfonamide
formation subsequent to Suzuki coupling (e.g., Example 250). The
sulfonamide formation can be executed via Schotten-Baumann
conditions (e.g., Example 251, Step 4) and/or using base (e.g.
triethylamine or Hunig's base) in polar aprotic solvent (e.g. DMF
or DMA) (as in Example 250, Step 5). For instance, Examples listed
in Table 4 were synthesized according to procedures analogous to
the synthesis of Example 1, Step 1 and 2, and Example 13. The data
are listed in Table 4.
TABLE-US-00004 TABLE 4 ##STR00172## LCMS Ex. Name --N(R).sub.2 [M +
H].sup.+ No. .sup.1H NMR Spectrum 47
3-(8-Aminoimidazo[1,2-a]pyrazin-3-yl)-N-
cyclopropyl-4-methylbenzenesulfonamide ##STR00173## 344.1 .sup.1H
NMR (d.sub.6-DMSO) .delta.: 7.99 (s, 1H), 7.96 (d, J = 2.7 Hz, 1H)
7.89 (dd, J = 8.1, 2.0 Hz, 1H), 7.77 (d, J = 2.0 Hz, 1H), 7.71 (d,
J = 8.2 Hz, 1H), 7.41 (d, J = 5.7 Hz, 1H), 7.27 (d, J = 5.7 Hz,
1H), 2.26 (s, 3H), 2.19-2.13 (m, 1H), 0.53-0.45 (m, 2H), 0.43-0.37
(m, 2H) 48 3-(8-Aminoimidazo[1,2-a]pyrazin-3-yl)-4-methyl-N-
(tetrahydrofuran-3-ylmethyl)benzenesulfonamide ##STR00174## 388.1
.sup.1H NMR (d.sub.6-DMSO) .delta.: 7.94 (s, 1H), 7.90 (dd, J =
8.1, 2.0 Hz, 1H), 7.85 (d, J = 7.2 Hz, 1H), 7.79 (d, J = 2.0 Hz,
1H), 7.68 (d, J = 8.2 Hz, 1H), 7.35 (d, J = 5.5 Hz, 1H), 7.28 (d, J
= 5.5 Hz, 1H), 3.75-3.68 (m, 2H), 3.26-3.18 (m, 4H), 2.25 (s, 3H),
1.56-1.50 (m, 1H), 1.41-1.31 (m, 2H) 49
3-(8-Aminoimidazo[1,2-a]pyrazin-3-yl)-4-methyl-N-
(tetrahydro-2H-pyran-4-yl)benzenesulfonamide ##STR00175## 388.1 50
3-(8-Aminoimidazo[1,2-a]pyrazin-3-yl)-N-(3-
hydroxypropyl)-4-methylbenzenesulfonamide ##STR00176## 362.1 51
1-{[3-(8-Aminoimidazo[1,2-a]pyrazin-3-yl)-4-
methylphenyl]sulfonyl}piperidin-4-ol ##STR00177## 388.1 .sup.1H NMR
(d.sub.6-DMSO) .delta.: 7.76 (dd, J = 8.1, 2.0 Hz, 1H), 7.70 (d, J
= 8.1 Hz, 1H), 7.68 (s, 1H), 7.65 (d, J = 2.0 Hz, 1H), 7.24 (d, J =
4.7 Hz, 1H), 7.21 (d, J = 4.7 Hz, 1H), 7.00 (s, 2H), 4.68 (s, 1H),
3.59-3.49 (m, 1H), 3.23-3.11 (m, 2H), 2.80-2.67 (m, 2H), 2.25 (s,
3H), 1.78-1.68 (m, 2H), 1.48-1.35 (m, 2H) 52
3-(8-Aminoimidazo[1,2-a]pyrazin-3-yl)-N-(trans-4-
hydroxycyclohexyl)-N,4- dimethylbenzenesulfonamide ##STR00178##
416.1 .sup.1H NMR (d.sub.6-DMSO) .delta.: 7.82 (dd, J = 8.1, 2.0
Hz, 1H), 7.71 (d, J = 2.0 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.65
(s, 1H), 7.23 (d, J = 4.7 Hz, 1H), 7.13 (d, J = 4.7 Hz, 1H), 7.01
(s, 2H), 4.50 (m, 1H), 3.70-3.58 (m, 1H), 3.28-3.22 (m, 1H), 2.66
(s, 3H), 2.22 (s, 3H), 1.81-1.70 (m, 2H), 1.49-1.37 (m, 2H), 1.27
(d, J = 11.9 Hz, 2H), 1.22-1.10 (m, 2H) 53
3-(8-Aminoimidazo[1,2-a]pyrazin-3-yl)-N-(trans-4-
methoxycyclohexyl)-4-methylbenzenesulfonamide ##STR00179## 416.1 54
3-(8-Aminoimidazo[1,2-a]pyrazin-3-yl)-N-(trans-3-
hydroxycyclobutyl)-4-methylbenzenesulfonamide ##STR00180## 374.1 55
tert-Butyl [trans-4-({[3-(8-aminoimidazo[1,2- a]pyrazin-3-yl)-4-
methylphenyl]sulfonyl}amino)cyclohexyl]carbamate ##STR00181## 501.1
56 3-(8-Aminoimidazo[1,2-a]pyrazin-3-yl)-N-[trans-3-
(hydroxymethyl)cyclobutyl]-4- methylbenzenesulfonamide ##STR00182##
388.1 57 3-(8-Aminoimidazo[1,2-a]pyrazin-3-yl)-N-[(3S,6R)-
6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]-4-
methylbenzenesulfonamide ##STR00183## 418.1 84
3-(8-aminoimidazo[1,2-a]pyrazin-3-yl)-N-(4,4-
difluorocyclohexyl)-4-methylbenzenesulfonamide ##STR00184## 422.1
85 3-(8-aminoimidazo[1,2-a]pyrazin-3-yl)-N-(trans-4-
hydroxy-4-methylcyclohexyl)-4- methylbenzenesulfonamide
##STR00185## 416.1 86 3-(8-aminoimidazo[1,2-a]pyrazin-3-yl)-N-((1-
(cyclopropanecarbonyl)piperidin-4-yl)methyl)-4-
methylbenzenesulfonamide ##STR00186## 469.1 .sup..dagger-dbl. or
.sup.B denotes that the compound named was prepared using Method B
(Scheme X).
Example 58.
N-(trans-4-Aminocyclohexyl)-3-(8-aminoimidazo[1,2-a]pyrazin-3-yl)-4-methy-
lbenzenesulfonamide
##STR00187##
[1031] tert-Butyl
[trans-4-({[3-(8-aminoimidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl]sulfonyl-
}amino)cyclohexyl]carbamate (Example 55) was treated with TFA/DCM
for 15 min. The reaction mixture was concentrated. Purification via
preparative HPLC on a C-18 column (pH 10, 15-33% 0.1%
MeCN/NH.sub.4OH (aq) over 5 min, 60 mL/min) afforded the title
compound (1.2 mg). LCMS for C.sub.19H.sub.25N.sub.6O.sub.2S
(M+H).sup.+: calculated m/z=401.2; found 401.3.
Example 59.
N-[trans-4-({[3-(8-Aminoimidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl]sulfon-
yl}amino)cyclohexyl]acetamide
##STR00188##
[1032] Step 1.
N-(trans-4-Aminocyclohexyl)-3-(8-aminoimidazo[1,2-a]pyrazin-3-yl)-4-methy-
lbenzenesulfonamide Hydrochloride
##STR00189##
[1034] tert-Butyl
[trans-4-({[3-(8-aminoimidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl]sulfonyl-
}amino)cyclohexyl]carbamate (18.9 mg, 0.037 mmol) was stirred with
4.0 M hydrogen chloride in 1,4-dioxane (1.0 mL, 4.0 mmol) at room
temperature for 15 min. Evaporation gave the title compound (17.0
mg). LCMS for C.sub.19H.sub.25N.sub.6O.sub.2S (M+H).sup.+:
calculated m/z=401.2; found 401.1.
Step 2.
N-[trans-4-({[3-(8-Aminoimidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl-
]sulfonyl}amino)cyclohexyl]acetamide
[1035] To a solution of
N-(trans-4-aminocyclohexyl)-3-(8-aminoimidazo[1,2-a]pyrazin-3-yl)-4-methy-
lbenzenesulfonamide hydrochloride (8.5 mg, 0.019 mmol) in methylene
chloride (0.64 mL) was added triethylamine (16.3 .mu.L, 0.117 mmol)
and acetyl chloride (2.1 .mu.L, 0.029 mmol). The reaction mixture
was stirred for 2 min and diluted with MeOH. Purification via
preparative HPLC on a C-18 column (pH 10, 17-37% 0.1%
MeCN/NH.sub.4OH (aq) over 5 min, 60 mL/min) afforded the title
compound as a white residue (3.4 mg). LCMS for
C.sub.21H.sub.27N.sub.6O.sub.3S (M+H).sup.+: calculated m/z=443.2;
found 443.1.
[1036] Examples 60 to 72 were synthesized according to procedures
analogous to the synthesis of Example 1, Steps 1 and 2, and Example
39. The data are listed in Table 5. Examples 215 to 248 were made
from the coupling of the corresponding amine and
3-(4-aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methylbenzene-1-sulfonyl
chloride (i.e., Method B). Example 174 was prepared using Method B
with tert-butyl (S)-2-(hydroxymethyl)piperazine-1-carboxylate. The
BOC intermediate (S)-tert-butyl
4-(3-(4-aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methylphenylsulfonyl)-2-
-(hydroxymethyl)piperazine-1-carboxylate was then stirred at room
temperature for 24 h with 2.0 M phosgene in toluene to prepare
Example 174.
TABLE-US-00005 TABLE 5 ##STR00190## LCMS Ex. Name N(R).sub.2 [M +
H].sup.+ No. .sup.1H NMR 60
3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-[trans-3-
(hydroxymethyl)cyclobutyl]-4-methylbenzenesulfonamide ##STR00191##
389.1 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.08 (s, 1H), 7.95
(d, J = 1.7 Hz, 1H), 7.89-7.81 (m, 1H), 7.73 (s, 1H), 7.58 (d, J =
8.1 Hz, 1H), 3.88 (m, 1H), 3.51 (d, J = 6.9 Hz, 2H), 2.37 (s, 3H),
2.23 (s, 1H), 2.04-1.93 (m, 4H). 61
3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-[cis-3-
(hydroxymethyl)cyclobutyl]-4-methylbenzenesulfonamide ##STR00192##
389.0 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.07 (s, 1H), 7.96
(d, J = 1.9 Hz, 1H), 7.89-7.83 (m, 1H), 7.73 (s, 1H), 7.58 (d, J =
8.1 Hz, 1H), 3.76-3.61 (m, 1H), 3.42 (d, J = 6.0 Hz, 2H), 2.37 (s,
3H), 2.19 (m, 2H), 2.00 (m, 1H), 1.64-1.51 (m, 2H). 62
3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-[(3S,6R)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-yl]-4-
methylbenzenesulfonamide ##STR00193## 419.1 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.08 (s, 1H), 8.01 (d, J = 1.9 Hz, 1H), 7.89
(dd, J = 8.1, 1.9 Hz, 1H), 7.75 (s, 1H), 7.60 (d, J = 8.2 Hz, 1H),
3.92 (d, J = 10.6 Hz, 1H), 3.46 (d, J = 4.9 Hz, 2H), 3.23-3.04 (m,
3H), 2.39 (s, 3H), 1.86 (s, 1H), 1.64 (d, J = 12.6 Hz, 1H),
1.48-1.23 (m, 2H). 63
3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(cis-4-
hydroxycyclohexyl)-4-methylbenzenesulfonamide ##STR00194## 403.1
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.06 (s, 1H), 8.00 (d, J
= 1.8 Hz, 1H), 7.89 (dd, J = 8.1, 1.9 Hz, 1H), 7.73 (s, 1H), 7.59
(d, J = 8.1 Hz, 1H), 3.75 (m, 1H), 3.22-3.13 (m, 1H), 2.38 (s, 3H),
1.74-1.60 (m, 4H), 1.60-1.44 (m, 4H). 64
3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-
cyclopropyl-4-methylbenzenesulfonamide ##STR00195## 345.1 65
3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(3-
hydroxypropyl)-4-methylbenzenesulfonamide ##STR00196## 363.1 66
1-{[3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-
methylphenyl]sulfonyl}piperidin-4-ol ##STR00197## 389.1 67
3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methyl-N-
(tetrahydrofuran-3-ylmethyl)benzenesulfonamide ##STR00198## 389.1
68 3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methyl-N-
(tetrahydro-2H-pyran-4-yl)benzenesulfonamide ##STR00199## 389.1
.sup.1H NMR (d.sub.6-DMSO) .delta. 8.05 (s, 1H), 7.88 (d, J = 2.0
Hz, 1H), 7.78 (s, 1H), 7.76 (dd, J = 8.0, 2.0 Hz, 1H), 7.59 (d, J =
8.1 Hz, 1H), 3.68-3.60 (m, 2H), 3.57-3.50 (m, 1H), 3.40-3.35 (m,
1H), 2.76-2.70 (m, 2H), 2.31 (s, 3H), 2.30-2.25 (m, 1H), 1.90-1.81
(m, 1H), 1.51- 1.41 (m, 1H) 69
3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(trans-4-
hydroxycyclohexyl)-N,4-dimethylbenzenesulfonamide ##STR00200##
417.1 70 3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(trans-4-
methoxycyclohexyl)-4-methylbenzenesulfonamide ##STR00201## 417.1 71
3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(trans-3-
hydroxycyclobutyl)-4-methylbenzenesulfonamide ##STR00202## 375.1 72
tert-Butyl [trans-4-({[3-(4-aminoimidazo[2,1-
f][1,2,4]triazin-7-yl)-4-
methylphenyl]sulfonyl}amino)cyclohexyl]carbamate ##STR00203## 502.1
87 3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-((1r,3r)-3-
cyano-3-methylcyclobutyl)-4-methylbenzenesulfonamide
trifluoroacetate salt ##STR00204## 398.0 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.35 (s, 1H), 8.26 (s, 1H), 8.14-8.06 (m,
2H), 7.93 (d, J = 1.3 Hz, 1H), 7.83 (s, 1H), 7.78 (dd, J = 8.1, 1.5
Hz, 1H), 7.62 (d, J = 8.2 Hz, 1H), 3.88-3.77 (m, 1H), 2.66-2.55 (m,
2H), 2.36 (s, 3H), 1.98-1.86 (m, 2H), 1.37 (s, 3H)
88.sup..dagger-dbl. Methyl
3-(3-(4-aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-
methylphenylsulfonamido)bicyclo[1.1.1]pentane-1- carboxylate
trifluoroacetate salt ##STR00205## 429.1 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.13 (s, 1H), 8.01 (d, J = 1.9 Hz, 1H), 7.88
(dd, J = 8.1, 1.9 Hz, 1H), 7.81 (s, 1H), 7.62 (d, J = 8.1 Hz, 1H),
3.66 (s, 3H), 2.42 (s, 3H), 2.12 (s, 6H) 89
3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-((1r,3r)-3-
cyanocyclobutyl)-4-methylbenzenesulfonamide trifluoroacetate salt
##STR00206## 384.1 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.45
(s, 1H), 8.34 (s, 1H), 8.18 (d, J = 8.1 Hz, 1H), 8.12 (s, 1H), 7.92
(d, J = 2.0 Hz, 1H), 7.84 (s, 1H), 7.78 (dd, J = 8.1, 2.0 Hz, 1H),
7.62 (d, J = 8.2 Hz, 1H), 4.01-3.91 (m, 1H), 3.22-3.10 (m, 1H),
2.43-2.35 (m, 2H), 2.35 (s, 3H), 2.25-2.15 (m, 2H).
90.sup..dagger-dbl.
3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(4-
cyanobicyclo[2.2.1]heptan-1-yl)-4- methylbenzenesulfonamide
trifluoroacetate salt ##STR00207## 424.1 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.38 (s, 1H), 8.29 (s, 1H), 8.24 (s, 1H),
8.09 (s, 1H), 7.97 (d, J = 1.9 Hz, 1H), 7.83 (s, 1H), 7.81 (dd, J =
8.1, 2.0 Hz, 1H), 7.61 (d, J = 8.1 Hz, 1H), 2.36 (s, 3H), 1.98-1.85
(m, 2H), 1.82 (s, 2H), 1.80-1.64 (m, 4H), 1.56-1.44 (m, 2H)
91.sup..dagger-dbl.
3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(3-
(cyanomethyl)bicyclo[1.1.1]pentan-1-yl)-4- methylbenzenesulfonamide
trifluoroacetate salt ##STR00208## 410.1 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.65 (s, 1H), 8.38 (s, 1H), 8.28 (s, 1H),
8.10 (s, 1H), 7.92 (d, J = 1.7 Hz, 1H), 7.82 (s, 1H), 7.79 (dd, J =
8.1, 1.8 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 2.81 (s, 2H), 2.35 (s,
3H), 1.74 (s, 6H) 92.sup..dagger-dbl.
N-(3-((1H-pyrazol-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)-
3-(4-aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-
methylbenzenesulfonamide trifluoroacetate salt ##STR00209## 451.3
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.56 (s, 1H), 8.45 (s,
1H), 8.34 (s, 1H), 8.07 (s, 1H), 7.88 (d, J = 1.9 Hz, 1H), 7.80 (s,
1H), 7.75 (dd, J = 8.1, 1.9 Hz, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.58
(d, J = 2.2 Hz, 1H), 7.38 (d, J = 1.7 Hz, 1H), 6.19 (t, J = 2.0 Hz,
1H), 4.21 (s, 2H), 2.34 (s, 3H), 1.61 (s, 6H) 93.sup..dagger-dbl.
3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(3-(2-
hydroxypropan-2-yl)bicyclo[1.1.1]pentan-1-yl)-4-
methylbenzenesulfonamide trifluoroacetate salt ##STR00210## 429.1
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.13 (s, 1H), 7.99 (d, J
= 1.8 Hz, 1H), 7.88 (dd, J = 8.1, 1.9 Hz, 1H), 7.80 (s, 1H), 7.61
(d, J = 8.1 Hz, 1H), 2.39 (s, 3H), 1.74 (s, 6H), 1.10 (s, 6H)
94.sup..dagger-dbl.
3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methyl-N-
(3-(3-methyl-1,2,4-oxadiazol-5-yl)bicyclo[1.1.1]pentan-1-
yl)benzenesulfonamide trifluoroacetate salt ##STR00211## 453.1
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.12 (s, 1H), 8.05 (d, J
= 1.6 Hz, 1H), 7.90 (dd, J = 8.1, 1.6 Hz, 1H), 7.81 (s, 1H), 7.64
(d, J = 8.1 Hz, 1H), 2.42 (s, 3H), 2.36 (s, 6H), 2.33 (s, 3H)
95.sup..dagger-dbl. N-(3-Acetylbicyclo[1.1.1]pentan-1-yl)-3-(4-
aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4- methylbenzenesulfonamide
trifluoroacetate salt ##STR00212## 413.2 .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta. 8.08 (s, 1H), 8.01 (d, J = 2.0 Hz, 1H), 7.88
(dd, J = 8.1, 2.0 Hz, 1H), 7.76 (s, 1H), 7.61 (d, J = 8.1 Hz, 1H),
2.40 (s, 3H), 2.11 (s, 6H), 2.10 (s, 3H) 96.sup..dagger-dbl.
3-(3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-
methylphenylsulfonamido)-N,N-
dimethylbicyclo[1.1.1]pentane-1-carboxamide trifluoroacetate salt
##STR00213## 442.2 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.69
(s, 1H), 8.42 (s, 1H), 8.31 (s, 1H), 8.09 (s, 1H), 7.94 (d, J = 1.8
Hz, 1H), 7.83 (s, 1H), 7.80 (dd, J = 8.1, 1.9 Hz, 1H), 7.63 (d, J =
8.2 Hz, 1H), 2.92 (s, 3H), 2.75 (s, 3H), 2.35 (s, 3H), 2.04 (s, 6H)
97.sup..dagger-dbl.
3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methyl-N-
(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1- yl)benzenesulfonamide
trifluoroacetate salt ##STR00214## 439.2 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.91 (s, 1H), 8.41 (s, 1H), 8.30 (s, 1H),
8.03 (s, 1H), 7.96 (d, J = 1.9 Hz, 1H), 7.84 (s, 1H), 7.81 (dd, J =
8.1, 2.0 Hz, 1H), 7.64 (d, J = 8.2 Hz, 1H), 2.37 (s, 3H), 2.03 (s,
6H) 98.sup..dagger-dbl.
3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(3-
fluorobicyclo[1.1.1]pentan-1-yl)-4- methylbenzenesulfonamide
trifluoroacetate salt ##STR00215## 389.1 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.10 (s, 1H), 7.99 (d, J = 1.8 Hz, 1H), 7.87
(dd, J = 8.1, 1.8 Hz, 1H), 7.79 (s, 1H), 7.62 (d, J = 8.2 Hz, 1H),
2.40 (s, 3H), 2.14 (d, J = 2.0 Hz, 6H) 99.sup..dagger-dbl.
N-(3-(1H-tetrazol-5-yl)bicyclo[1.1.1]pentan-1-yl)-3-(4-
aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4- methylbenzenesulfonamide
trifluoroacetate salt ##STR00216## 439.1 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.10 (s, 1H), 8.04 (d, J = 1.6 Hz, 1H), 7.92
(dd, J = 8.1, 1.7 Hz, 1H), 7.80 (s, 1H), 7.64 (d, J = 8.2 Hz, 1H),
2.41 (s, 3H), 2.36 (s, 6H) 100
3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methyl-N-
(2-methyltetrahydrofuran-3-yl)benzenesulfonamide trifluoroacetate
salt (mixture of diastereomers prepared) ##STR00217## 389.1 101
3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-((1-
cyanocyclopropyl)methyl)-4-methylbenzenesulfonamide
trifluoroacetate salt ##STR00218## 384.2 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.42 (s, 1H), 8.32 (s, 1H), 8.24 (t, J = 6.4
Hz, 1H), 8.10 (s, 1H), 7.91 (d, J = 1.7 Hz, 1H), 7.85-7.69 (m, 2H),
7.61 (d, J = 8.2 Hz, 1H), 2.95 (d, J = 6.4 Hz, 2H), 2.32 (s, 3H),
1.22-1.09 (m, 2H), 1.06-0.91 (m, 2H) 102
3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-((1-
cyanocyclobutyl)methyl)-4-methylbenzenesulfonamide trifluoroacetate
salt ##STR00219## 398.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
8.42 (s, 1H), 8.32 (s, 1H), 8.22 (t, J = 6.7 Hz, 1H), 8.10 (s, 1H),
7.95 (d, J = 1.9 Hz, 1H), 7.86-7.80 (m, 2H), 7.63 (d, J = 8.1 Hz,
1H), 3.14 (d, J = 6.7 Hz, 2H), 2.38-2.27 (m, 2H), 2.34 (s, 3H),
2.24-2.10 (m, 2H), 2.07-1.84 (m, 2H) 103
N-(1-Acetylazetidin-3-yl)-3-(4-aminoimidazo[1,2-
f][1,2,4]triazin-7-yl)-methylbenzenesulfonamide trifluoroacetate
salt ##STR00220## 402.1
104 3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methyl-N-
(oxetan-3-yl)benzenesulfonamide ##STR00221## 361.1 .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 8.54 (d, J = 8.1 Hz, 1H), 8.38 (s, 1H),
8.28 (s, 1H), 8.10 (s, 1H), 7.88 (d, J = 1.8 Hz, 1H), 7.82 (s, 1H),
7.77 (dd, J = 8.1, 1.9 Hz, 1H), 7.61 (d, J = 8.1 Hz, 1H), 4.54 (t,
J = 6.7 Hz, 2H), 4.41 (dq, J = 14.4, 7.6, 7.1 Hz, 1H), 4.28 (t, J =
6.3 Hz, 2H), 2.33 (s, 3H) 105.sup..dagger-dbl.
3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(3-
(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-4-
methylbenzenesulfonamide trifluoroacetate salt ##STR00222## 401.2
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.51 (s, 1H), 8.39 (s,
1H), 8.29 (s, 1H), 8.09 (s, 1H), 7.91 (d, J = 1.8 Hz, 1H), 7.80 (s,
1H), 7.78 (dd, J = 8.1, 1.9 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 3.35
(s, 2H), 2.34 (s, 3H), 1.60 (s, 6H) 106.sup..dagger-dbl.
3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-
(bicyclo[1.1.1]pentan-1-yl)-4-methylbenzenesulfonamide
trifluoroacetate salt ##STR00223## 371.1 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.11 (s, 1H), 7.98 (d, J = 1.9 Hz, 1H), 7.88
(dd, J = 8.1, 2.0 Hz, 1H), 7.79 (s, 1H), 7.60 (d, J = 8.1 Hz, 1H),
2.39 (s, 3H), 2.31 (s, 1H), 1.86 (s, 6H). 107.sup..dagger-dbl.
3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(4-
(hydroxymethyl)bicyclo[2.1.1]hexan-1-yl)-4-
methylbenzenesulfonamide trifluoroacetate salt ##STR00224## 415.2
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.11 (s, 1H), 8.00 (d, J
= 1.5 Hz, 1H), 7.90 (d, J = 8.2, 1.6 Hz, 1H), 7.78 (s, 1H), 7.59
(d, J = 8.1 Hz, 1H), 3.54 (s, 2H), 2.38 (s, 3H), 1.86-1.72 (m, 2H),
1.64-1.53 (m, 2H), 1.53-1.43 (m, 2H), 1.27-1.18 (m, 2H)
108.sup..dagger-dbl.
3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(4-
(cyanomethyl)bicyclo[2.1.1]hexan-1-yl)-4- methylbenzenesulfonamide
trifluoroacetate salt ##STR00225## 424.1 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.13 (s, 1H), 8.01 (d, J = 1.8 Hz, 1H), 7.90
(dd, J = 8.1, 1.9 Hz, 1H), 7.80 (s, 1H), 7.61 (d, J = 8.1 Hz, 1H),
2.66 (s, 2H), 2.39 (s, 3H), 1.89-1.80 (m, 2H), 1.67-1.61 (m, 2H),
1.61-1.53 (m, 2H), 1.43-1.31 (m, 2H) 109.sup..dagger-dbl.
4-(3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(4-
methylphenylsulfonamido)bicyclo[2.1.1]hexane-1- carboxylic acid
##STR00226## 429.2 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.49
(s, 1H), 8.36 (s, 1H), 8.26 (s, 1H), 8.07 (s, 1H), 7.96 (d, J = 1.8
Hz, 1H), 7.83-7.77 (m, 2H), 7.61 (d, J = 8.2 Hz, 1H), 2.35 (s, 3H),
1.81-1.62 (m, 6H), 1.43-1.30 (m, 2H) 110.sup..dagger-dbl.
4-(3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(4-
methylphenylsulfonamido)bicyclo[2.1.1]hexane-1- carboxamide
trifluoroacetate salt ##STR00227## 428.2 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.42 (s, 1H), 8.40 (s, 1H), 8.30 (s, 1H),
8.09 (s, 1H), 7.95 (d, J =1.8 Hz, 1H), 7.83-7.78 (m, 2H), 7.60 (d,
J = 8.2 Hz, 1H), 7.06 (s, 1H), 6.84 (s, 1H), 2.35 (s, 3H),
1.74-1.57 (m, 6H), 1.39-1.29 (m, 2H) 111.sup..dagger-dbl.
3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methyl-N-
(3-(oxazol-5-yl)bicyclo[1.1.1]pentan-1- yl)benzenesulfonamide
trifluoroacetate salt ##STR00228## 438.1 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.08 (s, 1H), 8.05 (s, 1H), 8.03 (d, J = 2.0
Hz, 1H), 7.90 (dd, J = 8.1, 1.9 Hz, 1H), 7.76 (s, 1H), 7.62 (d, J =
8.1 Hz, 1H), 6.88 (s, 1H), 2.41 (s, 3H), 2.20 (s, 6H)
112.sup..dagger-dbl.
N-(3-((1H-Imidazol-1-yl)methyl)bicyclo[1.1.1]pentan-1-
yl)-3-(4-aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-
methylbenzenesulfonamide trifluoroacetate salt ##STR00229## 451.1
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.07-8.98 (m, 1H), 8.68
(s, 1H), 8.38 (s, 1H), 8.29 (s, 1H), 8.08 (s, 1H), 7.91 (d, J = 1.9
Hz, 1H), 7.80 (s, 1H), 7.76 (dd, J = 8.1, 2.0 Hz, 1H), 7.68- 7.65
(m, 1H), 7.65-7.63 (m, 1H), 7.61 (d, J = 8.2 Hz, 1H), 4.35 (s, 2H),
2.34 (s, 3H), 1.68 (s, 6H) 113.sup..dagger-dbl.
N-(3-((1H-1,2,4-triazol-1-yl)methyl)bicyclo[1.1.1]pentan-1-
yl)-3-(4-aminoimidazol[1,2-f][1,2,4]triazin-7-yl)-4-
methylbenzenesulfonamide trifluoroacetate salt ##STR00230## 452.2
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.60 (s, 1H), 8.43 (s,
1H), 8.40 (s, 1H), 8.30 (s, 1H), 8.07 (s, 1H), 7.93 (s, 1H), 7.89
(d, J = 1.8 Hz, 1H), 7.79 (s, 1H), 7.75 (dd, J = 8.1, 1.9 Hz, 1H),
7.60 (d, J = 8.2 Hz, 1H), 4.31 (s, 2H), 2.34 (s, 3H), 1.64 (s, 6H)
114.sup..dagger-dbl.
3-(4-Aminoimidazol[1,2-f][1,2,4]triazin-7-yl)-4-methyl-N-
(3-(thiazol-2-yl)bicyclo[1.1.1]pentan-1- yl)benzenesulfonamide
trifluoroacetate salt ##STR00231## 454.1 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.12 (s, 1H), 8.05 (d, J = 1.9 Hz, 1H), 7.92
(dd, J = 8.1, 2.0 Hz, 1H), 7.83 (s, 1H), 7.71 (d, J = 3.3 Hz, 1H),
7.64 (d, J = 8.1 Hz, 1H), 7.51 (d, J = 3.3 Hz, 1H), 2.41 (s, 3H),
2.30 (s, 6H) 115.sup..dagger-dbl. Methyl
3-(3-(4-aminoimidazol[1,2-f][1,2,4]triazin-7-yl)-4-
methylphenylsulfonamido)bicyclo[1.1.1]pentan-1- ylcarbamate
trifluoroacetate salt ##STR00232## 444.2 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.61 (s, 1H), 8.41 (s, 1H), 8.31 (s, 1H),
8.11 (s, 1H), 7.92 (d, J = 1.8 Hz, 1H), 7.82 (s, 1H), 7.78 (dd, J =
8.0, 1.9 Hz, 1H), 7.62 (d, J = 8.2 Hz, 1H), 3.47 (s, 3H), 2.35 (s,
3H), 1.90 (s, 6H) 116.sup..dagger-dbl.
3-(4-Aminoimidazol[1,2-f][1,2,4]triazin-7-yl)-4-methyl-N-
(3-morpholinobicyclo[1.1.1]pentan-1- yl)benzenesulfonamide
trifluoroacetate salt ##STR00233## 456.2 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.09 (s, 1H), 8.01 (d, J = 2.0 Hz, 1H), 7.89
(dd, J = 8.1, 2.0 Hz, 1H), 7.76 (s, 1H), 7.63 (d, J = 8.1 Hz, 1H),
3.97-3.71 (m, 4H), 3.23-2.94 (m, 4H), 2.40 (s, 3H), 2.19 (s, 6H)
117.sup..dagger-dbl.
3-(4-Aminoimidazol[1,2-f][1,2,4]triazin-7-yl)-4-methyl-N-
(3-methylbicyclo[1.1.1]pentan-1-yl)benzenesulfonamide ##STR00234##
385.2 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.25 (s, 1H),
7.15 (s, 1H), 7.05 (d, J = 7.8 Hz, 1H), 6.92 (s, 1H), 6.78 (d, J =
8.0 Hz, 1H), 1.57 (s, 3H), 0.89 (s, 6H), 0.34 (s, 3H)
118.sup..dagger-dbl. N-(3-aminobicyclo[1.1.1]pentan-1-yl)-3-(4-
aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N,4-
dimethylbenzenesulfonamide trifluoroacetate salt ##STR00235## 400.1
.sup.1H NMR (600 MHz, CD.sub.3OD) .delta. 8.09 (s, 1H), 8.00 (d, J
= 2.0 Hz, 1H), 7.85 (dd, J = 8.1, 2.1 Hz, 1H), 7.78 (s, 1H), 7.66
(d, J = 8.2 Hz, 1H), 2.93 (s, 3H), 2.43 (s, 3H), 2.29 (s, 6H) 119
5-{[3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-
methylphenyl]sulfonyl}-5-azaspiro[2.5]octan-8-ol ##STR00236## 415.2
120 8-{[3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-
methylphenyl]sulfonyl}-8-azabicyclo[3.2.1]octan-3-ol ##STR00237##
415.2 121 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-{[4-
(hydroxymethyl)tetrahydro-2H-pyran-4-yl]methyl}-4-
methylbenzenesulfonamide ##STR00238## 433.3 122
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4,4-
difluorocyclohexyl)-4-methylbenzenesulfonamide ##STR00239## 423.1
123 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-[(3S,4R)-4-
hydroxytetrahydrofuran-3-yl]-4-methylbenzenesulfonamide
##STR00240## 391.1 124
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-[cis-4-
hydroxy-4-(trifluoromethyl)cyclohexyl]-4- methylbenzenesulfonamide
##STR00241## 471.1 125
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-[trans-4-(1-
hydroxy-1-methylethyl)cyclohexyl]-4- methylbenzenesulfonamide
##STR00242## 445.2 126
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-[3,3-
bis(hydroxymethyl)cyclobutyl]-4- methylbenzenesulfonamide
##STR00243## 419.1 127
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(trans-4-
hydroxy-1-methylcyclohexyl)-4-methylbenzenesulfonamide ##STR00244##
417.1 128 (1-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-
methylphenyl)sulfonyl)azetidin-3-yl)methanol ##STR00245## 375.1 129
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(2-(1,1-
dioxidothiomorpholino)ethyl)-4-methylbenzenesulfonamide
##STR00246## 466.1 130
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-((4,4-
difluorocyclohexyl)methyl)-4-methylbenzenesulfonamide ##STR00247##
437.1 131 7-(5-((3-fluoroazetidin-1-yl)sulfonyl)-2-
methylphenyl)imidazo[2,1-f][1,2,4]triazin-4-amine ##STR00248##
363.1 132 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(3,3-
difluorocyclobutyl)-4-methylbenzenesulfonamide ##STR00249## 395.0
133 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-((1S,4S)-4-
hydroxy-4-methylcyclohexyl)-4-methylbenzenesulfonamide ##STR00250##
417.2 134 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-((4-
fluorotetrahydro-2H-pyran-4-yl)methyl)-4- methylbenzenesulfonamide
##STR00251## 421.2 135
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-((1,1-
dioxidotetrahydrothiophen-3-yl)methyl)-4- methylbenzenesulfonamide
##STR00252## 437.2 136 3-(8-aminoimidazo[1,2-a]pyrazin-3-yl)-N-((1-
(cyclopropanecarbonyl)piperidin-4-yl)methyl)-4-
methylbenzenesulfonamide ##STR00253## 469.1 137
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(2-
hydrocyclohexyl)-4-methylbenzenesulfonamide ##STR00254## 403.2 138
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methyl-N-
(2-(2-oxopyrrolidin-1-yl)ethyl)benzenesulfonamide ##STR00255##
416.2 139 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-
methylbenzenesulfonamide ##STR00256## 305.1 140.sup.B
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-((1S,3S)-3-
hydroxy-3-(trifluoromethyl)cyclobutyl)-4- methylbenzenesulfonamide
##STR00257## 443.2 141.sup.B
2-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-
methylphenyl)sulfonyl)-6-(trifluoromethyl)-2-
azaspiro[3.3]heptan-6-ol ##STR00258## 469.2 142.sup.B
7-(5-((8-oxa-2-azaspiro[4.5]decan-2-yl)sulfonyl)-2-
methylphenyl)imidazo[2,1-f][1,2,4]triazin-4-amine ##STR00259##
429.2 143.sup.B
7-(5-((2-oxa-6-azaspiro[3.3]heptan-6-yl)sulfonyl)-2-
methylphenyl)imidazo[2,1-f][1,2,4]triazin-4-amine ##STR00260##
387.2 144.sup.B 1-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-
methylphenyl)sulfonyl)-3-cyclopropylazetidin-3-ol, TFA ##STR00261##
401.1 145.sup.B 2-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-
methylphenyl)sulfonyl)-2-azaspiro[3.3]heptan-6-ol, TFA
##STR00262##
401.1 146.sup.B 7-(2-methyl-5-((3-morpholinoazetidin-1-
yl)sulfonyl)phenyl)imidazo[2,1-f][1,2,4]triazin-4-amine, 2TFA
##STR00263## 430.1 147.sup.B
(S)-7-(5-((2-(methoxymethyl)pyrrolidin-1-yl)sulfonyl)-2-
methylphenyl)imidazo[2,1-f][1,2,4]triazin-4-amine ##STR00264##
403.2 148.sup.B 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-
cyclopropyl-N,4-dimethylbenzenesulfonamide ##STR00265## 359.2
149.sup.B 7-(5-((4-azaspiro[2.5]octan-4-yl)sulfonyl)-2-
methylphenyl)imidazo[2,1-f][1,2,4]triazin-4-amine ##STR00266##
399.2 150.sup.B
(R)-1-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-
methylphenyl)sulfonyl)pyrrolidine-3-carbonitrile ##STR00267## 384.2
151.sup.B 7-(5-(((3R,4R)-3-fluoro-4-methoxypyrrolidin-1-
yl)sulfonyl)-2-methylphenyl)imidazo[2,1-f][1,2,4]triazin-4- amine
##STR00268## 407.2 152.sup.B
(R)-(1-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-
methylphenyl)sulfonyl)pyrrolidin-2-yl)methanol ##STR00269## 389.2
153.sup.B 7-(2-methyl-5-((3-(oxetan-3-yl)azetidin-1-
yl)sulfonyl)phenyl)imidazo[2,1-f][1,2,4]triazin-4-amine
##STR00270## 401.2 154.sup.B
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(2-
cyanoethyl)-N,4-dimethylbenzenesulfonamide ##STR00271## 372.2
155.sup.B 7-(5-((3,5-dimethylmorpholino)sulfonyl)-2-
methylphenyl)imidazo[2,1-f][1,2,4]triazin-4-amine ##STR00272##
403.2 156.sup.B 7-(5-((3,3-dimethylmorpholino)sulfonyl)-2-
methylphenyl)imidazo[2,1-f][1,2,4]triazin-4-amine ##STR00273##
403.2 157.sup.B
(1-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-
methylphenyl)sulfonyl)-6-methylpiperidin-2-yl)methanol ##STR00274##
417.2 158.sup.B 7-(2-methyl-5-((2,5,5-
trimethylmorpholino)sulfonyl)phenyl)imidazo[2,1-
f][1,2,4]triazin-4-amine ##STR00275## 417.2 159.sup.B
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-((1R,3R)-3-
hydroxycyclobutyl)-N,4-dimethylbenzenesulfonamide ##STR00276##
389.2 160.sup.B 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-((1-
(hydroxymethyl)cyclopropyl)methyl)-N,4- dimethylbenzenesulfonamide
##STR00277## 403.2 161.sup.B
4-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-
methylphenyl)sulfonyl)thiomorpholine 1,1-dioxide ##STR00278## 423.2
162.sup.B 4-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-
methylphenyl)sulfonyl)-3-methylthiomorpholine 1,1- dioxide
##STR00279## 437.2 163.sup.B
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N,4-dimethyl-
N-(2,2,2-trifluoroethyl)benzenesulfonamide ##STR00280## 401.2
164.sup.B 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-
(cyclopropylmethyl)-4-methyl-N- propylbenzenesulfonamide
##STR00281## 401.2 165.sup.B
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(2-
cyanoethyl)-N-cyclopentyl-4-methylbenzenesulfonamide ##STR00282##
426.2 166.sup.B
(R)-(1-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-
methylphenyl)sulfonyl)piperazin-2-yl)methanol ##STR00283## 404.0
167.sup.B
(3S,4S)-1-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-
methylphenyl)sulfonyl)-4-(4-methylpiperazin-1- yl)pyrrolidin-3-ol
##STR00284## 473.2 168.sup.B
7-(5-((2-(3,5-dimethylisoxazol-4-yl)pyrrolidin-1-
yl)sulfonyl)-2-methylphenyl)imidazo[2,1-f][1,2,4]triazin-4- amine
##STR00285## 454.2 169.sup.B
7-(2-methyl-5-((3-morpholino-8-azabicyclo[3.2.1]octan-8-
yl)sulfonyl)phenyl)imidazo[2,1-f][1,2,4]triazin-4-amine
##STR00286## 484.2 170.sup.B 7-(2-methyl-5-(((1R,5S)-3-methyl-3,8-
diazabicyclo[3.2.1]octan-8-yl)sulfonyl)phenyl)imidazo[2,1-
f][1,2,4]triazin-4-amine ##STR00287## 414.2 171.sup.B
4-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-
methylphenyl)sulfonyl)-1-cyclopropylpiperazin-2-one ##STR00288##
428.2 172.sup.B
(R)-2-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-
methylphenyl)sulfonyl)octahydro-4H-pyrido[1,2-a]pyrazin- 4-one
##STR00289## 442.2 173.sup.B
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(2-
cyanoethyl)-N-cyclohexyl-4-methylbenzenesulfonamide ##STR00290##
440.2 174.sup.B
(R)-7-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-
methylphenyl)sulfonyl)hexahydro-3H-oxazolo[3,4- a]pyrazin-3-one
##STR00291## 430.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.35
(s, 1H), 8.26 (s, 1H), 8.08 (s, 1H), 7.87 (m, 2H), 7.71 (m, 2H),
4.34 (s, 1H), 3.95 (m, 2H), 3.84 (m, 1 H), 3.67 (m, 2H), 3.09 (m,
1H), 2.39 (s, 3H), 2.37 (m, 2H). 175.sup.B
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(2-
cyanoethyl)-N-(3-hydroxypropyl)-4- methylbenzenesulfonamide
##STR00292## 416.2 176.sup.B
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N,4-dimethyl-
N-((3-methyloxetan-3-yl)methyl)benzenesulfonamide ##STR00293##
403.2 177.sup.B 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(1-
(methoxymethyl)cyclopropyl)-N,4- dimethylbenzenesulfonamide
##STR00294## 403.2 178.sup.B
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-((1-
(hydroxymethyl)cyclobutyl)methyl)-N,4- dimethylbenzenesulfonamide
##STR00295## 417.2 179.sup.B
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-ethyl-4-
methyl-N-((tetrahydrofuran-2- yl)methyl)benzenesulfonamide
##STR00296## 417.2 180
3-(4-aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-
(bicyclo[2.2.1]heptan-1-yl)-4-methylbenzenesulfonamide
trifluoroacetate salt ##STR00297## 399.1 181
3-(4-aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-
(bicyclo[2.2.2]octan-1-yl)-4-methylbenzenesulfonamide
trifluoroacetate salt ##STR00298## 413.1 182
3-(4-aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methyl-N-
(quinuclidin-4-yl)benzenesulfonamide trifluoroacetate salt
##STR00299## 414.1 183
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-((3S,6R)-6-
(cyanomethyl)tetrahydro-2H-pyran-3-yl)-4- methylbenzenesulfonamide
##STR00300## 428.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.31
(br s, 1H), 8.23 (br s, 1H), 8.06 (s, 1H), 7.94 (s, 1H), 7.87-7.74
(m, 3H), 7.60 (d, J = 7.5 Hz, 1H), 3.72 (d, J = 7.5 Hz, 1H),
3.51-3.38 (m, 1H), 3.13-2.91 (m, 2H), 2.76-2.54 (m, 2H), 2.34 (s,
3H), 1.83-1.55 (m, 2H), 1.47-1.17 (m, 2H). 184.sup..dagger-dbl.
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(trans-4-
(cyanomethyl)cyclohexyl)-4-methylbenzenesulfonamide
trifluoroacetate ##STR00301## 426.3 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.34 (br s, 1H), 8.25 (br s, 2H), 8.06 (s,
1H), 7.91 (d, J = 1.9 Hz, 1H), 7.85-7.74 (m, 2H), 7.65 (d, J = 7.2
Hz, 1H), 7.58 (d, J = 8.2 Hz, 1H), 2.98- 2.80 (m, 1H), 2.37 (d, J =
6.5 Hz, 2H), 2.32 (s, 3H), 1.78-1.60 (m, 3H), 1.60-1.36 (m, 1H),
1.28-1.10 (m, 2H), 1.08-0.88 (m, 2H). 185.sup..dagger-dbl.
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-
hydroxybicyclo[2.2.2]octan-1-yl)-4- methylbenzenesulfonamide
##STR00302## 429.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.31
(br s, 1H), 8.23 (br s, 1H), 8.05 (s, 1H), 7.90 (s, 1H), 7.83-7.73
(m, 2H), 7.55 (d, J = 8.1 Hz, 1H), 7.46 (s, 1H), 4.23 (s, 1H), 4.23
(s, 1H), 2.32 (s, 3H), 1.81- 1.58 (m, 6H), 1.57-1.33 (m, 6H).
186.sup..dagger-dbl.
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-
(hydroxymethyl)bicyclo[2.2.2]octan-1-yl)-4-
methylbenzenesulfonamide ##STR00303## 443.2 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.31 (br s, 1H), 8.23 (br s, 1H), 8.05 (s,
1H), 7.91 (s, 1H), 7.86-7.68 (m, 2H), 7.55 (d, J = 7.8 Hz, 1H),
7.44 (s, 1H), 4.41-4.15 (m, 1H), 2.93 (d, J = 4.9 Hz, 2H), 2.32 (s,
3H), 1.74-1.46 (m, 6H), 1.40-1.08 (m, 6H). 187.sup..dagger-dbl.
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-
cyanobicyclo[2.2.2]octan-1-yl)-4- methylbenzenesulfonamide
##STR00304## 438.2 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
8.43-8.13 (m, 2H) 8.08 (s, 1H), 7.92 (s, 1H), 7.86-7.71 (m, 2H),
7.71-7.62 (m, 1H), 7.61-7.47 (m, 1H), 2.33 (s, 3H), 1.96-1.76 (m,
6H), 1.76- 1.51 (m, 6H). 188.sup..dagger-dbl.
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-
fluorobicyclo[2.2.2]octan-1-yl)-4- methylbenzenesulfonamide
##STR00305## 431.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
8.44-8.11 (m, 2H), 8.06 (s, 1H), 7.92 (d, J = 1.7 Hz, 1H),
7.84-7.72 (m, 2H), 7.56 (d, J = 8.2 Hz, 1H), 2.32 (s, 3H),
1.89-1.77 (m, 6H), 1.77-1.63 (m, 6H). 189.sup..dagger-dbl.
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(1-
cyanocyclopropyl)-4-methylbenzenesulfonamide ##STR00306## 370.1
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.08 (s, 1H), 8.36 (br
s, 1H), 8.26 (br s, 1H), 8.09 (s, 1H), 7.95 (s, 1H), 7.85-7.74 (m,
2H), 7.64 (d, J = 8.1 Hz, 1H), 2.34 (s, 3H), 1.50-1.35 (m, 2H),
1.32-1.15 (m, 2H). 190.sup..dagger-dbl.
2-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-
methylphenyl)sulfonamido)-2-methylpropanamide trifluoroacetate
##STR00307## 390.3 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.38
(br s, 1H), 8.28 (br s, 1H), 8.07 (s, 1H), 7.93 (d, J = 1.8 Hz,
1H), 7.86-7.77 (m, 2H), 7.75 (s, 1H), 7.56 (d, J = 8.2 Hz, 1H),
7.05 (d, J = 18.3 Hz, 2H), 2.31 (s, 3H), 1.23 (s, 6H).
191.sup..dagger-dbl.
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-((1s,3s)-3-
hydroxy-1-methylcyclobutyl)-4-methylbenzenesulfonamide ##STR00308##
389.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.31 (br s, 1H),
8.22 (br s, 1H), 8.06 (s, 1H), 7.90 (d, J = 1.9 Hz, 1H), 7.82 (s,
1H), 7.80-7.72 (m, 2H), 7.57 (d, J = 8.1 Hz, 1H), 4.95 (d, J = 5.7
Hz, 1H), 3.84 (M, 1H), 2.31 (s, 3H), 2.06 (M, 2H), 1.94 (M, 2H),
1.17 (s, 3H). 192.sup..dagger-dbl.
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(1-
cyanocyclobutyl)-4-methylbenzenesulfonamide trifluoroacetate
##STR00309## 384.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.86
(s, 1H), 8.39 (br s, 1H), 8.28 (br s, 1H), 8.08 (s, 1H), 7.94 (d, J
= 2.0 Hz, 1H), 7.85-7.74 (m, 2H), 7.62 (d, J = 8.2 Hz, 1H),
2.47-2.38 (m, 2H), 2.38-2.26 (m, 5H), 2.03-1.80 (m, 2H).
193.sup..dagger-dbl.
8-((3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-
methylphenyl)sulfonyl)-3-oxa-1,8-diazaspiro[4.5]decan-2- one
##STR00310## 444.1
194.sup..dagger-dbl.
7-(5-((1-Oxa-8-azaspiro[4.5]decan-8-yl)sulfonyl)-2-
methylphenyl)imidazo[2,1-f][1,2,4]triazin-4-amine ##STR00311##
429.2 195.sup..dagger-dbl.
2-((3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-
methylphenyl)sulfonyl)-6-methyl-2,6-diazaspiro[3.4]octan- 5-one
##STR00312## 428.2 196.sup..dagger-dbl.
1-((3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-
methylphenyl)sulfonyl)-4,4-difluoropiperidin-3-ol ##STR00313##
425.2 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.33 (br s, 1H),
8.24 (br s, 1H), 8.07 (s, 1H), 7.90 (d, J = 2.0 Hz, 1H), 7.85 (s,
1H), 7.76 (dd, J = 8.1, 2.0 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 5.93
(d, J = 5.7 Hz, 1H), 3.81 (br s, 1H), 3.26-3.13 (m, 2H), 3.04-2.97
(m, 1H), 2.96-2.88 (m, 1H), 2.38 (s, 3H), 2.30-2.10 (m, 1H),
2.09-1.89 (m, 1H). 197.sup..dagger-dbl.
(S)-1-((3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-
methylphenyl)sulfonyl)pyrrolidin-3-ol ##STR00314## 375.2
198.sup..dagger-dbl.
7-(5-((Hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)sulfonyl)-
2-methylphenyl)imidazo[2,1-f][1,2,4]triazin-4-amine ##STR00315##
414.2 199.sup..dagger-dbl.
N-(1-((3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-
methylphenyl)sulfonyl)pyrrolidin-3-yl)acetamide ##STR00316## 416.2
200.sup..dagger-dbl.
1-((3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-
methylphenyl)sulfonyl)-3-methylpyrrolidine-3-carbonitrile
##STR00317## 398.2 201.sup..dagger-dbl.
7-(2-Methyl-5-((3-(pyridin-4-yl)pyrrolidin-1-
yl)sulfonyl)phenyl)imidazo[2,1-f][1,2,4]triazin-4-amine
##STR00318## 436.2 202.sup..dagger-dbl.
7-(5-((1-Oxa-7-azaspiro[4.4]nonan-7-yl)sulfonyl)-2-
methylphenyl)imidazo[2,1-f][1,2,4]triazin-4-amine ##STR00319##
415.1 203.sup..dagger-dbl.
7-(5-((7-Oxa-2-azaspiro[4.5]decan-2-yl)sulfonyl)-2-
methylphenyl)imidazo[2,1-f][1,2,4]triazin-4-amine ##STR00320##
429.1 204.sup..dagger-dbl.
7-(5-((3-(Dimethylamino)pyrrolidin-1-yl)sulfonyl)-2-
methylphenyl)imidazo[2,1-f][1,2,4]triazin-4-amine ##STR00321##
402.1 205.sup..dagger-dbl.
7-(5-((1-Oxa-6-azaspiro[3.4]octan-6-yl)sulfonyl)-2-
methylphenyl)imidazo[2,1-f][1,2,4]triazin-4-amine ##STR00322##
401.1 206.sup..dagger-dbl.
7-(2-Methyl-5-((1-methyl-8-oxa-2-azaspiro[4.5]decan-2-
yl)sulfonyl)phenyl)imidazo[2,1-f][1,2,4]triazin-4-amine
##STR00323## 443.1 207.sup..dagger-dbl.
7-(5-((8,8-Difluoro-2-azaspiro[4.5]decan-2-yl)sulfonyl)-2-
methylphenyl)imidazo[2,1-f][1,2,4]triazin-4-amine ##STR00324##
463.1 208.sup..dagger-dbl.
7-(5-((7-Oxa-1-azaspiro[4.4]nonan-1-yl)sulfonyl)-2-
methylphenyl)imidazo[2,1-f][1,2,4]triazin-4-amine ##STR00325##
415.1 209.sup..dagger-dbl.
7-(5-((8-Oxa-1-azaspiro[4.5]decan-1-yl)sulfonyl)-2-
methylphenyl)imidazo[2,1-f][1,2,4]triazin-4-amine ##STR00326##
429.1 210.sup..dagger-dbl.
7-(5-((Hexahydropyrano[3,4-c]pyrrol-2(3H)-yl)sulfonyl)-2-
methylphenyl)imidazo[2,1-f][1,2,4]triazin-4-amine ##STR00327##
415.1 211.sup..dagger-dbl.
7-(5-((cis-Hexahydro-5H-furo[2,3-c]pyrrol-5-yl)sulfonyl)-
2-methylphenyl)imidazo[2,1-f][1,2,4]triazin-4-amine ##STR00328##
401.1 212.sup..dagger-dbl.
(S)-(1-((3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-
methylphenyl)sulfonyl)-4,4-difluoropyrrolidin-2- yl)methanol
##STR00329## 425.1 213.sup..dagger-dbl.
(S)-2-(1-((3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-
methylphenyl)sulfonyl)pyrrolidin-2-yl)propan-2-ol ##STR00330##
417.2 214 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methyl-N-
(1,3,5-trimethyl-1H-pyrazol-4-yl)benzenesulfonamide ##STR00331##
413.2 215.sup.B 7-(5-((6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-
yl)sulfonyl)-2-methylphenyl)imidazo[2,1-f][1,2,4]triazin-4- amine
##STR00332## 411.2 216.sup.B
7-(2-methyl-5-((4-(pyridin-2-yl)piperidin-1-
yl)sulfonyl)phenyl)imidazo[2,1-f][1,2,4]triazin-4-amine
##STR00333## 450.2 217.sup.B
1-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-
methylphenyl)sulfonyl)piperdine-4-carbonitrile ##STR00334## 398.2
218.sup.B 7-(2-methyl-5-((3-(trifluoromethyl)piperidin-1-
yl)sulfonyl)phenyl)imidazo[2,1-f][1,2,4]triazin-4-amine
##STR00335## 441.2 219.sup.B
7-(2-methyl-5-((3-(tetrahydrofuran-3-yl)azetidin-1-
yl)sulfonyl)phenyl)imidazo[2,1-f][1,2,4]triazin-4-amine
##STR00336## 415.1 220.sup.B
7-(5-((6-oxa-2-azaspiro[3.4]octan-2-yl)sulfonyl)-2-
methylphenyl)imidazo[2,1-f][1,2,4]triazin-4-amine ##STR00337##
401.1 221.sup.B 7-(5-((-2-oxa-6-azaadamantan-6-yl)sulfonyl)-2-
methylphenyl)imidazo[2,1-f][1,2,4]triazin-4-amine ##STR00338##
427.1 222.sup.B
7-(2-methyl-5-((8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-
a]pyrazin-7(8H)-yl)sulfonyl)phenyl)imidazo[2,1-
f][1,2,4]triazin-4-amine ##STR00339## 426.2 223.sup.B
7-(5-((5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-
yl)sulfonyl)-2-methylphenyl)imidazo[2,1-f][1,2,4]triazin-4- amine
##STR00340## 411.1 224.sup.B
7-(2-methyl-5-((3,4,6,7-tetrahydro-5H-imidazo[4,5-
c]pyridin-5-yl)sulfonyl)phenyl)imidazo[2,1-f][1,2,4]triazin-
4-amine ##STR00341## 411.2 225.sup.B
7-(2-methyl-5-((2-methyl-2,4,6,7-tetrahydro-5H-
pyrazolo[4,3-c]pyridin-5-yl)sulfonyl)phenyl)imidazo[2,1-
f][1,2,4]triazin-4-amine ##STR00342## 425.3 226.sup.B
N-(1-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-
methylphenyl)sulfonyl)piperidin-4-yl)acetamide ##STR00343## 430.2
227.sup.B 1-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-
methylphenyl)sulfonyl)-N-methylpiperidine-4-carboxamide
##STR00344## 430.2 228.sup.B
4-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-
methylphenyl)sulfonyl)-1-methylpiperazin-2-one ##STR00345## 402.2
229.sup.B 1-(4-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-
methylphenyl)sulfonyl)piperazin-1-yl)ethan-1-one ##STR00346## 416.3
230.sup.B 7-(2-methyl-5-((4-(pyrimidin-2-yl)piperazin-1-
yl)sulfonyl)phenyl)imidazo[2,1-f][1,2,4]triazin-4-amine
##STR00347## 452.1 231.sup.B
3-(4-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-
methylphenyl)sulfonyl)piperazin-1-yl)pyrazine-2- carbonitrile
##STR00348## 477.2 232.sup.B
6-(4-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-
methylphenyl)sulfonyl)piperazin-1-yl)nicotinonitrile ##STR00349##
476.2 233.sup.B
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methyl-N-
(pyrazin-2-ylmethyl)benzenesulfonamide ##STR00350## 397.1 234.sup.B
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methyl-N-
(2,2,2-trifluoro-1-(pyridin-2-yl)ethyl)benzenesulfonamide
##STR00351## 464.1 235.sup.B
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methyl-N-
((6-(trifluoromethyl)pyridin-2- yl)methyl)benzenesulfonamide
##STR00352## 464.1 236.sup.B
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methyl-N-
((1-methyl-1H-pyrazol-5-yl)methyl)benzenesulfonamide ##STR00353##
399.1 237.sup.B
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methyl-N-
((5-methyl-1,2,4-oxadiazol-3- yl)methyl)benzenesulfonamide
##STR00354## 401.1 238.sup.B
N-(2-amino-1-cyclopropylethyl)-3-(4-aminoimidazo[2,1-
f][1,2,4]triazin-7-yl)-4-methylbenzenesulfonamide ##STR00355##
388.3 239.sup.B
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methyl-N-
(2-methyl-1-(pyrrolidin-1-yl)propan-2- yl)benzenesulfonamide
##STR00356## 430.2 240.sup.B
5-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-
methylphenyl)sulfonyl)-4,5,6,7-tetrahydropyrazolo[1,5-
a]pyrazine-3-carbonitrile ##STR00357## 436.2 241.sup.B
7-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-
methylphenyl)sulfonyl)-N-(2,2,2-trifluoroethyl)-5,6,7,8-
tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide ##STR00358## 536.2
242.sup.B 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(6-(3-
hydroxyazetidine-1-carbonyl)pyridin-3-yl)-4-
methylbenzenesulfonamide ##STR00359## 481.2 243.sup.B
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methyl-N-
(1H-pyrazolo[3,4-c]pyridin-5-yl)benzenesulfonamide ##STR00360##
422.1 244.sup.B
N-(5-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-
methylphenyl)sulfonamido)pyridin-2-yl)acetamide ##STR00361## 439.2
245.sup.B 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methyl-N-
(4-methylpyridin-3-yl)benzenesulfonamide ##STR00362## 396.1
246.sup.B 3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(6-
methoxy-2-methylpyridin-3-yl)-4- methylbenzenesulfonamide
##STR00363## 426.1 247.sup.B
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N,4-dimethyl-
N-(pyridin-4-yl)benzenesulfonamide ##STR00364## 396.2 248.sup.B
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(2-
cyanopyridin-4-yl)-4-methylbenzenesulfonamide ##STR00365## 407.2
.sup..dagger-dbl. or .sup.B denotes that the compound named was
prepared using Method B (Scheme X).
Example 73.
N-(trans-4-Aminocyclohexyl)-3-(8-aminoimidazo[1,2-a]pyrazin-3-yl)-4-methy-
lbenzenesulfonamide Bis-Hydrochloride
##STR00366##
[1038] The title compound was synthesized according to experimental
procedures analogous to the synthesis of Example 59, Step 1
substituting tert-butyl
[trans-4-({[3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl]s-
ulfonyl}amino)cyclohexyl]carbamate (Example 72) for tert-butyl
[trans-4-({[3-(8-aminoimidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl]sulfonyl-
}amino)cyclohexyl]carbamate. LCMS for
C.sub.18H.sub.24N.sub.7O.sub.2S (M+H).sup.+: calculated m/z=402.2;
found 402.1.
Example 74.
N-[trans-4-({[3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl-
]sulfonyl}amino)cyclohexyl]acetamide
##STR00367##
[1040] The title compound was synthesized according to experimental
procedures analogous to the synthesis of Example 59, Step 2
substituting
N-(trans-4-aminocyclohexyl)-3-(8-aminoimidazo[1,2-a]pyrazin-3-yl)-4-methy-
lbenzenesulfonamide bis-hydrochloride (Example 73) for
N-(trans-4-aminocyclohexyl)-3-(8-aminoimidazo[1,2-a]pyrazin-3-yl)-4-methy-
lbenzenesulfonamide hydrochloride (Example 59). .sup.1H NMR
(d.sub.6-DMSO) .delta.: 8.06 (s, 1H), 7.91 (d, J=2.0 Hz, 1H), 7.78
(s, 1H), 7.78-7.77 (m, 1H), 7.76 (d, J=2.0 Hz, 1H), 7.63 (d, J=7.7
Hz, 1H), 7.58 (d, J=8.2 Hz, 1H), 3.38-3.33 (m, 2H), 2.98-2.88 (m,
2H), 2.32 (s, 3H), 1.72 (s, 3H), 1.67 (d, J=10.0 Hz, 2H), 1.25-1.14
(m, 2H), 1.12-1.01 (m, 2H). LCMS for
C.sub.20H.sub.26N.sub.7O.sub.3S (M+H).sup.+: calculated m/z=444.2;
found 444.1.
Example 249.
(S)-3-(4-Amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-N-(1-
-hydroxypropan-2-yl)-4-methylbenzenesulfonamide
##STR00368##
[1041] Step 1.
(S)-3-Bromo-N-(1-hydroxypropan-2-yl)-4-methylbenzenesulfonamide
##STR00369##
[1043] To a mixture of (S)-2-aminopropan-1-ol (55.7 mg, 0.742 mmol,
Aldrich) and triethylamine (0.16 mL, 1.1 mmol) in DCM (4.0 mL) at
0.degree. C. was added dropwise a solution of
3-bromo-4-methylbenzenesulfonyl chloride (100.0 mg, 0.371 mmol,
Enamine) in DCM (2.0 mL). The reaction mixture was stirred for one
hr at 0.degree. C. Solvent was removed in vacuo and the product was
purified by flash chromatography, eluting with a gradient from
0-17% EtOAc in hexanes to afford a colorless oil (0.096 g, 84%).
LCMS for C.sub.10H.sub.15BrNO.sub.3S (M+H).sup.+: calculated
m/z=308.0; found 307.9.
Step 2.
(S)-N-(1-hydroxypropan-2-yl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-
-dioxaborolan-2-yl)benzenesulfonamide
##STR00370##
[1045] A degassed mixture of
(S)-3-bromo-N-(1-hydroxypropan-2-yl)-4-methylbenzenesulfonamide (96
mg, 0.31 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (103
mg, 0.405 mmol), potassium acetate (101 mg, 1.03 mmol) and
dichlorobis(triphenylphosphine)-palladium(II) (8.8 mg, 0.012 mmol)
in THF (1.5 mL) was heated in a microwave at 140.degree. C. for 20
minutes. The reaction mixture was cooled to room temperature,
diluted with EtOAc and filtered through Celite.TM., rinsing with
EtOAc. The filtrate was washed with water and then brine, dried
over Na.sub.2SO.sub.4, filtered, and concentrated. Purification via
flash chromatography, eluting with a gradient of 0-50% EtOAc in
hexanes afforded product as a clear oil (0.136 g, theoretical yield
assumed). LCMS for C.sub.1-6H.sub.27BNO.sub.5S (M+H).sup.+:
calculated m/z=356.2; found 356.2.
Step 3. 2-(Trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-4-ol
##STR00371##
[1047] Ethyl 1-amino-1H-imidazole-2-carboxylate (3.22 g, 20.8 mmol,
prepared as in US2015/0274767) and trifluoroacetamidine (9.36 mL,
125 mmol, Oakwood) in EtOH (86 mL) were stirred in an oil bath held
at 95.degree. C. for 96 hours. The reaction mixture was allowed to
cool to room temperature and the white solid product was isolated
by filtration (1.42 g, 34%). LCMS for C.sub.6H.sub.4F.sub.3N.sub.4O
(M+H).sup.+: calculated m/z=205.0; found 205.1. .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 7.77 (s, 1H), 7.49 (s, 1H).
Step 4.
7-Bromo-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-4-ol
##STR00372##
[1049] A solution of
2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-ol (1.46 g, 7.19
mmol) in DMF (25 mL) was treated with NBS (1.41 g, 7.91 mmol) for 1
h. The reaction mixture was diluted with water (100 mL), acidified
to pH 2 using 1 N HCl, and was extracted with EtOAc twice. The
combined organic extracts were washed with water (3.times.100 mL)
and brine (100 mL), dried over Na.sub.2SO.sub.4, filtered and
concentrated to afford a white solid (1.92 g, 95%). LCMS for
C.sub.6H.sub.3BrF.sub.3N.sub.4O (M+H).sup.+: calculated m/z=282.9,
284.9; found 283.0, 285.0. .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 7.67 (s, 1H).
Step 5.
7-Bromo-4-chloro-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazine
##STR00373##
[1051] 7-Bromo-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-ol
(1.92 g, 6.80 mmol) was heated to 110.degree. C. in POCl.sub.3
(20.0 mL, 215 mmol) for 30 minutes. Upon cooling to room
temperature, POCl.sub.3 was removed in vacuo. The residue was
poured into a mixture of ice water. The aqueous mixture was made
basic by the addition of sat'd NaHCO.sub.3 solution, and the
mixture was extracted with EtOAc (3.times.). The combined organic
extracts were dried over sodium sulfate, filtered and concentrated.
The product was used without further purification in the next step
(2.0 g, 98%). LCMS for C.sub.6H.sub.2BrClF.sub.3N.sub.4(M+H).sup.+:
calculated m/z=300.9, 302.9; found 301.0, 303.0.
Step 6.
7-Bromo-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-4-amine
##STR00374##
[1053] A suspension of
7-bromo-4-chloro-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazine
(2.0 g, 6.6 mmol) in ammonium hydroxide (23 mL, 330 mmol, 14.8 M
NH.sub.4OH) was heated to 80.degree. C. in oil bath for 45 minutes.
Upon cooling to room temperature, water was added and the mixture
was extracted with EtOAc (3.times.). The combined organic extracts
were dried over Na.sub.2SO.sub.4, filtered and concentrated to
afford an off-white solid (1.7 g, 92%). LCMS for
C.sub.6H.sub.4BrF.sub.3N.sub.5(M+H).sup.+: calculated m/z=282.0,
284.0; found 282.0, 284.0. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.72 (s, 1H), 6.75 (br s, 1H), 6.46 (br s, 1H).
Step 7.
(S)-3-(4-Amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-y-
l)-N-(1-hydroxypropan-2-yl)-4-methylbenzenesulfonamide
[1054] A microwave vial was charged with
(S)-N-(1-hydroxypropan-2-yl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxab-
orolan-2-yl)benzenesulfonamide (80.0 mg, 0.18 mmol, from Step 2),
7-bromo-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-amine (51
mg, 0.18 mmol),
dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II)
dichloromethane adduct (29.0 mg, 0.036 mmol) and THF (14.0 mL) was
added followed by the addition of 1 M potassium carbonate solution
(0.72 mL, 0.72 mmol). The reaction mixture was degassed with
N.sub.2 and then heated in a microwave at 140.degree. C. for 30
minutes. The reaction mixture was diluted with MeOH and filtered
through a plug of Na.sub.2SO.sub.4 and Celite.TM.. The filtrate was
concentrated. The product was purified by preparative HPLC-MS (pH
2) to afford 49 mg white solid which suffered some formation of
trifluoroacetate ester. The product was then treated with aq.
NH.sub.4OH in MeCN, and was repurified by preparative HPLC-MS (pH
10) to afford product as the free base (24 mg, 31%). LCMS for
C.sub.1-6H.sub.18F.sub.3N.sub.6O.sub.3S (M+H).sup.+: calculated
m/z=431.1; found 431.2. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
8.51 (br s, 2H), 7.96-7.87 (m, 2H), 7.83 (dd, J=8.1, 2.0 Hz, 1H),
7.62 (d, J=8.2 Hz, 1H), 4.67 (br s, 1H), 3.36-3.28 (m, 1H),
3.20-3.10 (m, 2H), 2.33 (s, 3H), 0.92 (d, 3H).
Example 250.
3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(3-cyanobicyclo[1.1.1]pent-
an-1-yl)-4-methylbenzenesulfonamide
##STR00375##
[1055] Step 1.
3-((tert-Butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylic
Acid
##STR00376##
[1057] A mixture of 3-aminobicyclo[1.1.1]pentane-1-carboxylic acid,
HCl (500.0 mg, 3.06 mmol, PharmaBlock) and
N,N-diisopropylethylamine (1.0 mL, 6.1 mmol) in THF (10 mL) and
water (10 mL) was treated with di-tert-butyl dicarbonate (667 mg,
3.06 mmol). After stirring overnight, the reaction was treated with
1 N HCl to achieve pH 2 and was extracted with EtOAc. The combined
organic extracts were washed with water, brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated to afford a white solid
(665 mg, 96%). LCMS for C.sub.IIH.sub.17NO.sub.4Na (M+Na).sup.+:
calculated m/z=250.1; found 250.1.
Step 2. tert-Butyl
3-carbamoylbicyclo[1.1.1]pentan-1-ylcarbamate
##STR00377##
[1059] A solution of
3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylic
acid (660 mg, 2.90 mmol) in THF (15 mL) was treated with
triethylamine (0.49 mL, 3.5 mmol). The resulting mixture was cooled
to -15.degree. C. and ethyl chloroformate (0.31 mL, 3.2 mmol) was
added and the mixture was stirred for 1 h. To the mixture was added
ammonium hydroxide (19.5 mL, 145 mmol) solution. After stirring for
3 hours, THF was evaporated and to the white crude solid was added
water. The aqueous suspension was extracted with EtOAc (3.times.).
The combined organic extracts (fine suspension) were dried over
Na.sub.2SO.sub.4, and decanted (rather than filtered). The liquid
decanted was concentrated to afford a white solid (0.65 g, 100%).
LCMS for C.sub.11H.sub.18N.sub.2O.sub.3Na (M+Na).sup.+: calculated
m/z=249.1, found 249.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
7.50 (br s, 1H), 7.21 (s, 1H), 6.91 (s, 1H), 2.02 (s, 6H), 1.38 (s,
9H).
Step 3. Tert-Butyl 3-cyanobicyclo[1.1.1]pentan-1-ylcarbamate
##STR00378##
[1061] tert-Butyl (3-carbamoylbicyclo[1.1.1]pentan-1-yl)carbamate
(200.0 mg, 0.884 mmol) in DCM and triethylamine (0.370 mL, 2.65
mmol) at 0.degree. C. was treated with trichloroacetyl chloride
(0.15 mL, 1.3 mmol). After 30 minutes, additional triethylamine
(0.37 mL, 3.0 eq) and trichloroacetyl chloride (0.15 mL, 1.5 eq)
were added. After 30 minutes, the reaction was quenched by the
addition of sat'd. NaHCO.sub.3 solution and the aqueous mixture was
extracted with EtOAc. The combined organic extracts were dried over
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified by flash chromatography, eluting with a gradient from
0-100% EtOAc in hexanes and ELSD was used to detect the product
which was isolated as a white solid (107 mg, 58%). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 5.08 (s, 1H), 2.49 (s, 6H), 1.46 (s,
9H).
Step 4. 3-Aminobicyclo[1.1.1]pentane-1-carbonitrile, Hydrochloric
Acid Salt
##STR00379##
[1063] tert-Butyl (3-cyanobicyclo[1.1.1]pentan-1-yl)carbamate
(0.050 g, 0.24 mmol) was stirred for 2 hours in 4 M HCl in dioxane
(3.0 mL, 12.0 mmol). Volatiles were removed in vacuo to afford
product (32 mg, 92%). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
2.61 (s, 6H).
Step 5.
3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(3-cyanobicyclo[1.1-
.1]pentan-1-yl)-4-methylbenzenesulfonamide
[1064] To 3-aminobicyclo[1.1.1]pentane-1-carbonitrile, HCl salt
(0.160 g, 1.11 mmol, prepared as in Step 4) and triethylamine (0.46
mL, 3.3 mmol) in DMA (15 mL) at 0.degree. C. was added
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylbenzenesulfonyl
chloride (0.358 g, 1.11 mmol, Prepared as in Example 424, Step 7).
The reaction was stirred for 2 hours at 0.degree. C. The reaction
mixture was poured into pH 7 buffer and EtOAc. The layers were
separated and the aqueous layer was extracted with two further
portions of EtOAc. The combined organic extracts were washed with
water (3.times.), followed by brine, dried over sodium sulfate,
filtered and concentrated. The product was purified by preparative
HPLC-MS (pH 2) then repurified at (pH 10) (163 mg, 37%). LCMS for
C.sub.18H.sub.18N.sub.7O.sub.2S (M+H).sup.+: calculated m/z=396.1;
found 396.1. .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. 8.36 (s,
1H), 8.26 (s, 1H), 8.07 (s, 1H), 7.93 (d, J=2.0 Hz, 1H), 7.83 (s,
1H), 7.79 (dd, J=8.1, 2.0 Hz, 1H), 7.63 (d, J=8.2 Hz, 1H), 2.36 (s,
3H), 2.27 (s, 6H).
Example 251.
3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexa-
n-1-yl)-4-methylbenzenesulfonamide Trifluoroacetate Salt
##STR00380##
[1065] Step 1.
3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylic
Acid
##STR00381##
[1067] A solution of
4-((tert-butoxycarbonyl)amino)bicyclo[2.1.1]hexane-1-carboxylic
acid (250 mg, 1.04 mmol) (Spirochem catalog #SPC-a643) and
triethylamine (0.17 mL, 1.2 mmol) in THF (5 mL) at -15.degree. C.
was treated with ethyl chloroformate (0.109 mL, 1.14 mmol) and the
reaction was stirred for 1 hour. To the mixture was added ammonium
hydroxide (14.8 M, 7.0 mL, 52 mmol) in one portion. The reaction
mixture was stirred at room temperature overnight. THF was
evaporated, and to the white crude solid was added water. The
aqueous suspension was extracted with EtOAc (3.times.). The
combined organic extracts were dried over Na.sub.2SO.sub.4,
filtered and concentrated to afford product as a white solid (219
mg, 88%). LCMS for C.sub.12H.sub.21N.sub.2O.sub.3 (M+H).sup.+:
calculated m/z=241.2, found 241.3. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.30 (br s, 1H), 7.07 (s, 1H), 6.83 (s, 1H),
1.93 (br, 2H), 1.70 (s, 4H), 1.49 (s, 2H), 1.38 (s, 9H).
Step 2. tert-Butyl (4-cyanobicyclo[2.1.1]hexan-1-yl)carbamate
##STR00382##
[1069] tert-Butyl (4-carbamoylbicyclo[2.1.1]hexan-1-yl)carbamate
(290 mg, 1.21 mmol) in DCM (20 mL) containing triethylamine (1.35
mL, 9.65 mmol) at 0.degree. C. was treated with trichloroacetyl
chloride (0.54 mL, 4.8 mmol). After 40 minutes, the reaction was
quenched with saturated NaHCO.sub.3 at 0.degree. C. and the aqueous
mixture was extracted with DCM. The organic extract was dried over
MgSO.sub.4, filtered and concentrated, and the residue was purified
by flash chromatography (eluting with a gradient from 0-20%
EtOAc/hexanes) to afford product as a white solid (230 mg, 86%).
LCMS for C.sub.12H.sub.19N.sub.2O.sub.2 (M+H).sup.+: calculated
m/z=223.1, found 223.1. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
2.35 (br, 2H), 2.06-1.98 (m, 2H), 1.90-1.82 (m, 2H), 1.82-1.78 (m,
2H), 1.45 (s, 9H).
Step 3. 4-Aminobicyclo[2.1.1]hexane-1-carbonitrile, Hydrochloric
Acid Salt
##STR00383##
[1071] tert-Butyl (4-cyanobicyclo[2.1.1]hexan-1-yl)carbamate (0.99
g, 4.45 mmol, prepared as in Step 2) was dissolved in DCM (50 mL)
and 4 N HCl in dioxane (11.1 mL, 44 mmol) was added. The mixture
was stirred overnight and volatiles were removed in vacuo to afford
product as a white solid (0.7 g, 100%). LCMS for
C.sub.7H.sub.11N.sub.2(M+H).sup.+: calculated m/z=123.1, found
123.2. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.03 (s, 3H),
2.26-2.20 (m, 2H), 2.11-2.06 (m, 2H), 1.89-1.82 (m, 4H).
Step 4.
3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-.sup.7-yl)-N-(4-cyanobicycl-
o[2.1.1]hexan-1-yl)-4-methylbenzenesulfonamide, Trifluoroacetate
Salt
[1072] 1 M Sodium carbonate (0.43 mL, 0.43 mmol) was added to a
mixture of 4-aminobicyclo[2.1.1]hexane-1-carbonitrile, HCl salt
(20.6 mg, 0.130 mmol) in DCM (0.6 mL) and acetonitrile (0.3 mL).
The mixture was stirred for 5 minutes, then
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylbenzenesulfonyl
chloride (35 mg, 0.11 mmol, prepared as in Example 424, Step 7) was
added and the reaction was stirred overnight. Purification via
preparative HPLC-MS (pH 2) afforded product as the 1.4.times.TFA
salt (44 mg, 71%). LCMS for C.sub.19H.sub.20N.sub.7O.sub.2S
(M+H).sup.+: calculated m/z=410.1, found 410.1. .sup.1H NMR (600
MHz, DMSO-d.sub.6) .delta. 8.69 (s, 1H), 8.45 (s, 1H), 8.34 (s,
1H), 8.10 (s, 1H), 7.96 (d, J=2.1 Hz, 1H), 7.85 (s, 1H), 7.81 (dd,
J=8.1, 2.1 Hz, 1H), 7.62 (d, J=8.2 Hz, 1H), 2.36 (s, 3H), 2.01-1.93
(m, 2H), 1.92-1.85 (m, 2H), 1.74-1.66 (m, 2H), 1.63-1.55 (m,
2H).
Example 252.
3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-N-(4-hydroxybic-
yclo[2.1.1]hexan-1-yl)-4-(methyl-d.sub.3)benzenesulfonamide
##STR00384##
[1073] Step 1. 4-Aminobicyclo[2.1.1]hexane-1-carboxylic Acid
##STR00385##
[1075] To
4-((tert-Butoxycarbonyl)amino)bicyclo[2.1.1]hexane-1-carboxylic
acid (200.0 mg, 0.829 mmol, Spirochem) was added 4 N HCl in dioxane
(1.0 mL, 4.0 mmol) and the reaction was stirred for 3 hours.
Volatiles were removed in vacuo and the product was used crude in
the next step (117 mg, 100%).
Step 2. 4-Hydroxybicyclo[2.1.1]hexane-1-carboxylic Acid
##STR00386##
[1077] Sodium nitrite (182 mg, 2.63 mmol) in water (0.2 mL) was
added dropwise to a 10.degree. C. mixture of
4-aminobicyclo[2.1.1]hexane-1-carboxylic acid (117 mg, 0.829 mmol)
and 10% acetic acid in water (1.2 mL). The mixture was then heated
to 65.degree. C. and stirred at this temperature overnight. The
reaction mixture was then cooled to 5.degree. C. and potassium
hydroxide (370 mg, 6.6 mmol) in MeOH (0.8 mL) was added dropwise.
The reaction was again heated to 65.degree. C. for 3 hours. The
reaction mixture was cooled to room temperature and water was
added. The aqueous mixture was washed with EtOAc (2.times.). The
aqueous layer was cooled to 0.degree. C. and acidified by the
addition of 1 N HCl to pH 3. This acidic aqueous mixture was
extracted with EtOAc (4.times.). The organic extracts of the acidic
aqueous layer were dried over MgSO.sub.4, filtered and concentrated
to afford product which was used without further purification (80.0
mg, 68%).
Step 3. Benzyl (4-hydroxybicyclo[2.1.1]hexan-1-yl)carbamate
##STR00387##
[1079] 4-Hydroxybicyclo[2.1.1]hexane-1-carboxylic acid (70.0 mg,
0.49 mmol) in toluene (1 mL) was cooled to 10.degree. C. and was
treated with benzyl alcohol (230 .mu.L, 2.2 mmol). The reaction
mixture was then treated with DIEA (150 .mu.L, 0.86 mmol) and
diphenylphosphoryl azide (115 .mu.L, 0.54 mmol). The reaction
mixture was then slowly heated to 110.degree. C. overnight. The
reaction mixture was concentrated to remove solvent and was
partitioned between EtOAc and brine. The organic layer was dried
over MgSO.sub.4, filtered and concentrated. The residue was
slurried in DCM and filtered to remove reagent byproducts and the
filtrate was purified by flash chromatography, eluting with a
gradient of 0-100% EtOAc in hexanes (50.0 mg, 41%). .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 7.47-7.15 (m, 5H), 5.14-5.01 (m, 2H),
1.88-1.77 (m, 4H), 1.76-1.72 (m, 2H), 1.72-1.63 (m, 2H).
Step 4. 4-Aminobicyclo[2.1.1]hexan-1-ol, Hydrochloric Acid Salt
##STR00388##
[1081] To a solution of benzyl
(4-hydroxybicyclo[2.1.1]hexan-1-yl)carbamate (25 mg, 0.10 mmol) in
MeOH (2 mL) and water (1 mL) was added palladium (10 mg of 10% on
carbon) and the reaction mixture was shaken under H.sub.2 at 30 psi
for 3 hours. The reaction mixture was filtered and MeOH was removed
in vacuo. The resulting aqueous mixture was adjusted to pH 3 by the
addition of 1 N HCl and was washed with EtOAc to remove impurities.
The aqueous mixture was then lyophilized to afford product as the
HCl salt (7.0 mg, 47%).
Step 5.
3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-N-(4-hyd-
roxybicyclo[2.1.1]hexan-1-yl)-4-(methyl-d.sub.3)benzenesulfonamide
[1082] 4-Aminobicyclo[2.1.1]hexan-1-ol HCl salt (7 mg, 0.047 mmol)
and DIPEA (8.17 .mu.L, 0.047 mmol) were combined in DCM (0.6 mL)
and cooled to 0.degree. C. After stirring for 5 minutes,
3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-(methyl-d.sub-
.3)benzenesulfonyl chloride (14.7 mg, 0.037 mmol, prepared as in
Example 253, Steps 1 through 3, using
3-bromo-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-8-amine in Step 1)
in 0.5 mL DMA was added. The reaction was allowed to warm to room
temperature and the mixture was purified by preparative HPLC-MS (pH
10) to afford product as the free base (5.0 mg, 23%). LCMS for
C.sub.20H.sub.18D.sub.3F.sub.3N.sub.5O.sub.3S (M+H).sup.+:
calculated m/z=471.1, found 471.2. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.30 (br s, 1H), 7.86 (dd, J=8.1, 2.0 Hz,
1H), 7.83-7.80 (m, 2H), 7.71 (br s, 2H), 7.67 (d, J=8.1 Hz, 1H),
7.58 (s, 1H), 5.59 (br s, 1H), 1.65-1.57 (m, 2H), 1.48-1.40 (m,
4H), 1.37-1.31 (m, 2H).
Example 253.
3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexa-
n-1-yl)-4-(methyl-d.sub.3)benzenesulfonamide (Crystalline Free
Base)
##STR00389##
[1083] Step 1.
4,4,5,5-Tetramethyl-2-(2-(methyl-d.sub.3)phenyl)-1,3,2-dioxaborolane
##STR00390##
[1085] A degassed mixture of 1-bromo-2-(methyl-d.sub.3)benzene
(0.57 g, 3.3 mmol, Combiphos catalog #032D),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.25
g, 4.91 mmol, Aldrich), potassium acetate (1.06 g, 10.8 mmol) and
1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride
dichloromethane complex (0.214 g, 0.262 mmol, Aldrich) in dioxane
(16.4 mL) was heated to 110.degree. C. for 3 hours. The reaction
mixture was cooled to room temperature, diluted with DCM and
filtered through Celite.RTM., and the filtrate was concentrated.
Purification via flash chromatography, eluting with a gradient of
0-10% EtOAc in hexanes afforded product (647 mg, 89%). LCMS for
C.sub.13H.sub.17D.sub.3BO.sub.2 (M+H).sup.+: calculated m/z=222.2,
found 222.2.
Step 2.
7-(2-(methyl-d.sub.3)phenyl)imidazo[2,1-f][1,2,4]triazin-4-amine
##STR00391##
[1087] A microwave vial was charged with
4,4,5,5-tetramethyl-2-(2-(methyl-d.sub.3)phenyl)-1,3,2-dioxaborolane
(0.34 g, 1.5 mmol), 7-bromoimidazo[2,1-f][1,2,4]triazin-4-amine
(0.395 g, 1.85 mmol, Synthonix),
dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II)
dichloromethane adduct (0.251 g, 0.308 mmol, Aldrich) and THF (10
mL) was added followed by the addition of 1 M aq. K.sub.2CO.sub.3
(4.6 mL, 4.6 mmol). The reaction mixture was degassed with N.sub.2
and heated in an oil bath at 90.degree. C. for 4 hours, then
continued overnight at 80.degree. C. Upon cooling to room
temperature, the mixture was filtered and the solid white product
(160 mg) was washed with DCM. Further product was isolated by
removing solvent from the filtrate and isolation of the solid by
filtration, washing with water and DCM (total: 217 mg, 62%). LCMS
for C.sub.12H.sub.9D.sub.3N.sub.5(M+H).sup.+: calculated m/z=229.1,
found 229.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.20 (s,
2H), 8.04 (s, 1H), 7.68 (s, 1H), 7.52-7.23 (m, 4H).
Step 3.
3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-(methyl-d.sub.3)ben-
zenesulfonyl Chloride
##STR00392##
[1089]
7-(2-(methyl-d.sub.3)phenyl)imidazo[2,1-f][1,2,4]triazin-4-amine
(214 mg, 0.937 mmol) in DCM (2 mL) was stirred at 0.degree. C. for
10 minutes. Chlorosulfonic acid (0.44 mL, 6.6 mmol) was added
dropwise. The ice bath was removed, and the reaction mixture was
allowed to warm to room temperature. After 2.5 hours at room
temperature, the mixture was heated for 2 hours in an 50.degree. C.
oil bath. Upon cooling, the reaction mixture was diluted with DCM
(5 mL) and added to a stirring mixture of ice (10 g) and DCM (10
mL) kept in an ice-bath. The precipitated product was isolated by
filtration and rinsed with DCM. The biphasic filtrate was extracted
with DCM (2.times.), and the combined organic extracts were dried
over Na.sub.2SO.sub.4, filtered, and concentrated and the solid so
obtained was combined with the initial solid product isolated by
filtration (total: 253 mg light yellow solid powder, 83%). LCMS for
C.sub.12H.sub.8D.sub.3ClN.sub.5O.sub.2S (M+H).sup.+: calculated
m/z=327.0, found 327.1.
Step 4.
3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-.sup.7-yl)-N-(4-cyanobicycl-
o[2.1.1]hexan-1-yl)-4-(methyl-d.sub.3)benzenesulfonamide
[1090] To 4-aminobicyclo[2.1.1]hexane-1-carbonitrile, HCl (2.60 g,
16.4 mmol, prepared as in Example 251, Step 3) in a mixture of DCM
(82 mL) and acetonitrile (82 mL) was added 1 M aq. Na.sub.2CO.sub.3
(65 mL, 65 mmol). After stirring for 5 minutes,
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-(methyl-d.sub.3)benzenesul-
fonyl chloride (5.62 g, 17.2 mmol, prepared as in Step 3) was
added. The suspension was stirred overnight. EtOAc (300 mL) and
brine (150 mL) were added. The layers were separated and the
aqueous layer was extracted with EtOAc (4.times.300 mL). The
combined EtOAc extracts were dried over Na.sub.2SO.sub.4, filtered
and concentrated to give crude product as an off-white solid (5.8
g). The product was purified by flash chromatography in batches,
eluting with a slow gradient of 0-5% MeOH in DCM to give a white
solid (5.1 g). The purified product was then slurried in acetone
(51 mL) overnight. The product as the crystalline free base was
isolated by filtration and air dried to afford the desired product
as a white powder (4.5 g, 66%). Crystalline free base was
characterized by XRPD. The X-Ray Powder Diffraction (XRPD) was
obtained from Bruker D2 PHASER X-ray Powder Diffractometer (XRPD)
instrument. The general experimental procedures for XRPD were: (1)
X-ray radiation from copper at 1.054056 Awith K.sub..beta. filter
and LYNXEYE.TM. detector; (2) X-ray power at 30 kV, 10 mA; and (3)
the sample powder was dispersed on a zero-background sample holder.
The general measurement conditions for XRPD were: Start Angle 5
degrees; Stop Angle 30 degrees; Sampling 0.015 degrees; and Scan
speed 2 degree/min. The XRPD pattern is shown in FIG. 1 and the
XRPD data are provided in Table 6. LCMS for
C.sub.19H.sub.17D.sub.3N.sub.7O.sub.2S (M+H).sup.+: calculated
m/z=413.2, found 413.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
8.68 (s, 1H), 8.34 (s, 1H), 8.25 (s, 1H), 8.08 (s, 1H), 7.97 (d,
J=2.0 Hz, 1H), 7.83 (s, 1H), 7.81 (dd, J=8.1, 2.1 Hz, 1H), 7.62 (d,
J=8.1 Hz, 1H), 2.03-1.93 (m, 2H), 1.93-1.81 (m, 2H), 1.78-1.67 (m,
2H), 1.67-1.55 (m, 2H). Crystalline free base was characterized by
DSC. The DSC was obtained from TA Instruments Differential Scanning
Calorimetry, Model Q2000 with autosampler. The DSC instrument
conditions were as follows: 10-300.degree. C. at 10.degree. C./min;
Tzero aluminum sample pan and lid; and nitrogen gas flow at 50
mL/min. The DSC thermogram is shown in FIG. 2. The DSC thermogram
revealed one endothermal event at an onset temperature of
232.6.degree. C. with a peak temperature of 234.0.degree. C. which
is believed to be the melting/decomposition of the compound.
Crystalline free base was characterized by TGA. The TGA was
obtained from PerkinElmer Thermogravimetric Analyzer, Model Pyris
1. The general experimental conditions for TGA were: ramp from
20.degree. C. to 300.degree. C. at 10.degree. C./min; nitrogen
purge gas flow at 60 mL/min; ceramic crucible sample holder. The
TGA thermogram is shown in FIG. 3. A weight loss of about 0.4%
between 150.degree. C. and 250.degree. C. which is believed to be
the decomposition. The compound further decomposes above
250.degree. C.
TABLE-US-00006 TABLE 6 2-Theta (.degree.) Net Intensity Relative
Intensity (%) 7.9 1446 6.4 8.4 2441 10.9 9.3 770 3.4 10.5 1655 7.4
12.0 2110 9.4 12.3 1167 5.2 12.5 828 3.7 12.7 275 1.2 13.0 143 0.6
13.5 1778 7.9 14.4 329 1.5 15.3 2464 11.0 15.7 283 1.3 16.5 858 3.8
16.9 22415 100 17.3 2564 11.4 17.6 6542 29.2 17.4 2272 10.1 18.6
873 3.9 18.8 340 1.5 19.4 2394 10.7 19.9 1960 8.7 20.6 3902 17.4
21.0 616 2.7 21.1 561 2.5 21.3 324 1.4 21.9 700 3.1 22.2 548 2.4
22.6 169 0.8 23.2 1528 6.8 23.6 278 1.2 23.9 1350 6.0 24.1 1139 5.1
24.4 1049 4.7 24.9 8538 38.1 25.5 1651 7.4 26.1 291 1.3 26.2 469
2.1 26.5 3588 16.0 27.1 1837 8.2 27.6 169 0.8 28.1 168 0.7 28.6 900
4.0 29.3 180 0.8
Example 254.
3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexa-
n-1-yl)-4-(methyl-d.sub.3)benzenesulfonamide Crystalline
Hydrochloric Acid Salt
##STR00393##
[1092] Hydrochloric acid (1.07 mL, 2.67 mmol) (2.5 M solution in
EtOH) was added to a suspension of
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexa-
n-1-yl)-4-(methyl-d.sub.3)benzenesulfonamide (1.0 g, 2.4 mmol, from
Example 253) in acetone (40.0 mL). The solvent was removed from the
solution in vacuo to afford a solid. Ethyl acetate (9.9 mL, 100
mmol) was added and the mixture was stirred at room temperature for
2.5 hours. The solid was isolated by filtration and dried on funnel
under house vacuum for 2 hours, followed by overnight under
vacuum/N.sub.2 stream. (1.02 g, 94%). The hydrochloric acid salt
was shown to be a 1:1 salt by chloride titration and was
characterized by XRPD. Experimental parameters for acquiring the
XRPD data are as described in Example 253. The XRPD pattern is
shown in FIG. 4 and the XRPD data are provided in Table 7. LCMS for
C.sub.19H.sub.17D.sub.3N.sub.7O.sub.2S (M+H).sup.+: calculated
m/z=413.2, found 413.0. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
8.91 (s, 1H), 8.75 (s, 1H), 8.74 (s, 1H), 8.20 (s, 1H), 7.99 (s,
1H), 7.96 (d, J=2.0 Hz, 1H), 7.84 (dd, J=8.1, 2.1 Hz, 1H), 7.64 (d,
J=8.1 Hz, 1H), 2.02-1.93 (m, 2H), 1.92-1.84 (m, 2H), 1.74-1.66 (m,
2H), 1.63-1.56 (m, 2H). Crystalline hydrochloric acid salt was
characterized by DSC. Experimental parameters for acquiring the DSC
data are as described in Example 253. The DSC thermogram is shown
in FIG. 5. The DSC thermogram revealed one major endothermal event
at an onset temperature of 211.3.degree. C. with a peak temperature
of 233.4.degree. C. which is believed to be the
melting/decomposition of the compound. Crystalline hydrochloric
acid salt was characterized by TGA. Experimental parameters for
acquiring the TGA data are as described in Example 253. The TGA
thermogram is shown in FIG. 6. A weight loss of about 6.8% below
220.degree. C. in the first step and a weight loss of about 2.7%
between 220.degree. C. and 300.degree. C. in the second step were
observed and believed to be associated with the decomposition of
the compound.
TABLE-US-00007 TABLE 7 2-Theta (.degree.) Net Intensity Relative
Intensity (%) 7.1 228 3.8 9.7 563 9.4 9.9 1507 25.2 11.3 57 0.9
12.5 205 3.4 13.4 4704 78.6 14.1 1625 27.1 15.1 445 7.4 15.6 348
5.8 15.8 1475 24.6 16.1 3276 54.7 16.2 1874 31.3 16.5 1138 19.0
17.4 5988 100 18.0 4434 74.0 19.3 746 12.5 19.9 378 6.3 20.9 384
6.4 21.3 711 11.9 21.7 1938 32.4 22.0 3390 56.6 22.4 1107 18.5 23.4
776 13.0 23.9 83 1.4 24.5 1039 17.4 25.3 804 13.4 26.4 805 13.4
26.8 1201 20.1 27.9 1298 21.7 29.2 598 10.0
Example 255.
3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexa-
n-1-yl)-4-(methyl-d.sub.3)benzenesulfonamide Crystalline
Benzenesulfonic Acid Salt
##STR00394##
[1094] To
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2-
.1.1]hexan-1-yl)-4-(methyl-d.sub.3)benzenesulfonamide (1.00 g,
2.424 mmol, from Example 253) in acetone (40.0 mL) was added
benzenesulfonic acid in THF (1 M, 2.67 mL, 2.67 mmol) to obtain a
solution. The acetone was removed in vacuo and the solid was
slurried in ethyl acetate (10 mL) and was stirred for 1.5 hours.
The solid was isolated by filtration, washed with a small amount of
EtOAc and hexanes. The solid product was air dried for 2 hours and
under vacuum/N.sub.2 stream overnight at 50.degree. C. (1.3 g,
94%). The benzenesulfonic acid salt was shown to be a 1:1 salt by
.sup.1H NMR and was characterized by XRPD. Experimental parameters
for acquiring the XRPD data are as described in Example 253. The
XRPD pattern is shown in FIG. 7 and the XRPD data are provided in
Table 8. LCMS for C.sub.19H.sub.17D.sub.3N.sub.7O.sub.2S
(M+H).sup.+: calculated m/z=413.2, found 413.1. .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 8.30 (s, 1H), 8.04 (d, J=2.0 Hz, 1H), 8.01
(s, 1H), 7.93 (dd, J=8.2, 2.1 Hz, 1H), 7.88-7.82 (m, 2H), 7.65 (d,
J=8.2 Hz, 1H), 7.48-7.40 (m, 3H), 2.15-2.05 (m, 2H), 1.99-1.91 (m,
2H), 1.86-1.79 (m, 2H), 1.69-1.60 (m, 2H). Crystalline besylate
salt was characterized by DSC. Experimental parameters for
acquiring the DSC data are as described in Example 253. The DSC
thermogram is shown in FIG. 8. The DSC thermogram revealed one
endothermal event at an onset temperature of 211.0.degree. C. with
a peak temperature of 213.8.degree. C. which is believed to be the
melting/decomposition of the compound. Crystalline besylate salt
was characterized by TGA. Experimental parameters for acquiring the
TGA data are as described in Example 253. The TGA thermogram is
shown in FIG. 9. A weight loss of about 0.4% between 150.degree. C.
and 230.degree. C. was observed in the first step and followed by a
significant weight loss above 230.degree. C. which is believed to
be associated with the decomposition of the compound.
TABLE-US-00008 TABLE 8 2-Theta (.degree.) Net Intensity Relative
Intensity (%) 6.5 1795 26.7 8.0 374 5.6 8.9 83 1.2 9.9 5204 77.5
10.5 5702 84.9 11.2 809 12.0 12.2 477 7.1 13.1 621 9.3 14.3 808
12.0 14.8 3627 54.0 15.8 3818 56.9 16.5 4198 62.5 16.7 6714 100
17.1 4294 64.0 17.3 1001 14.9 17.9 591 8.8 18.6 2402 35.8 18.9 4034
60.1 19.2 2278 33.9 19.8 2131 31.7 20.3 1593 23.7 21.0 694 10.3
21.2 1626 24.2 21.8 918 13.7 22.2 2303 34.3 22.8 3238 48.2 23.6
2104 31.3 23.9 729 10.9 24.5 2109 31.4 24.9 2275 33.9 26.0 726 10.8
25.9 1789 26.6 26.3 986 14.7 26.8 353 5.3 27.1 197 2.9 27.7 562 8.4
28.5 1018 15.2 28.7 572 8.5 29.2 482 7.2 29.7 569 8.5
Example 256.
5-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexa-
n-1-yl)-6-methylpyridine-3-sulfonamide Trifluoroacetate Salt
##STR00395##
[1095] Step 1. 5-Bromo-6-methylpyridine-3-sulfonyl Chloride
##STR00396##
[1097] A round-bottom flask was charged with water (7.5 mL, 41
mmol) and cooled in an ice bath. To this was added thionyl chloride
(1.23 mL, 16.9 mmol) over 15 minutes. The reaction mixture was then
warmed to room temperature using a warm water bath, and copper(I)
chloride (0.018 g, 0.18 mmol) was added. The reaction mixture was
placed in a brine-ice bath.
[1098] Concurrently in a separate round-bottom flask,
5-bromo-6-methylpyridin-3-amine (0.686 g, 3.67 mmol, Combi-Blocks)
was dissolved in 12 N HCl (7.3 mL, 88 mmol). After a few minutes,
white solids were observed. This mixture was also placed in a
brine-ice bath. A solution of sodium nitrite (0.278 g, 4.03 mmol)
in water (0.99 mL, 55 mmol) was added over 1-2 minutes, giving
dissolution of solids. After stirring for 5 minutes, this mixture
was slowly added (over 5 minutes) to the thionyl chloride solution
generated above. After 2 hours, the reaction mixture was warmed to
room temperature and stirred for 1 hour. DCM (15 mL) and DI water
(25 mL) were added to the reaction mixture. Solid sodium
bicarbonate (11.1 g, 132 mmol) was added in portions until pH 7.
Water and ethyl acetate were added and the layers were separated.
The aqueous layer was extracted with EtOAc (2.times.). The combined
organic extracts were washed with brine, dried with magnesium
sulfate, filtered, and concentrated to give a brown oil, which was
used without further purification (440 mg, 44%).
Step 2.
5-Bromo-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-6-methylpyridine-3-sul-
fonamide
##STR00397##
[1100] 4-Aminobicyclo[2.1.1]hexane-1-carbonitrile, HCl salt (36 mg,
0.23 mmol) in DCM (2 mL) containing DIPEA (0.097 mL, 0.55 mmol) was
cooled to 0.degree. C. and stirred for 5 minutes, at which time
5-bromo-6-methylpyridine-3-sulfonyl chloride (50.0 mg, 0.185 mmol,
from Step 1) in DCM (0.5 mL) was added. After 1 hour, water was
added and the layers were separated. The aqueous layer was
extracted with EtOAc (3.times.). The combined organic extracts were
washed with brine, dried over MgSO.sub.4, filtered and
concentrated. The product was purified by flash chromatography,
eluting with a gradient from 0-100% EtOAc in hexanes to provide
desired product as a clear oil (50.0 mg, 62%). LCMS for
C.sub.13H.sub.15BrN.sub.3O.sub.2S (M+H).sup.+: calculated
m/z=356.0, found 356.1. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
8.84 (d, J=2.0 Hz, 1H), 8.37 (d, J=2.0 Hz, 1H), 2.75 (s, 3H),
2.19-2.07 (m, 2H), 2.01-1.94 (m, 2H), 1.85-1.74 (m, 2H), 1.74-1.62
(m, 2H).
Step 3.
N-(4-Cyanobicyclo[2.1.1]hexan-1-yl)-6-methyl-5-(4,4,5,5-tetramethy-
l-1,3,2-dioxaborolan-2-yl)pyridine-3-sulfonamide
##STR00398##
[1102] A microwave vial was charged with bis(pinacolato)diboron
(0.036 g, 0.14 mmol, Aldrich), potassium acetate (0.045 g, 0.46
mmol) and
5-bromo-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-6-methylpyridine-3-sulfonamid-
e (0.050 g, 0.14 mmol) as a solution in THF (2 mL). The reaction
mixture was sparged with nitrogen for 5 minutes. To this mixture
was added bis(triphenylphosphine)palladium(II)chloride (0.099 g,
0.14 mmol), and the mixture was sealed and heated to 80.degree. C.
overnight. Upon cooling to room temperature, the reaction mixture
was diluted with EtOAc and washed with water. The organic layer was
washed with brine, dried over MgSO.sub.4, filtered and concentrated
to afford product, which was used without further purification (55
mg, 97%). LCMS for C.sub.19H.sub.27BN.sub.3O.sub.4S (M+H).sup.+:
calculated m/z=404.2, found 404.1.
Step 4.
5-(4-Aminoimidazo[2,1-f][1,2,4]triazin-.sup.7-yl)-N-(4-cyanobicycl-
o[2.1.1]hexan-1-yl)-6-methylpyridine-3-sulfonamide,
Trifluoroacetate Salt
[1103] To a degassed mixture of
7-bromoimidazo[2,1-f][1,2,4]triazin-4-amine (6.4 mg, 0.030 mmol),
1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride
dichloromethane complex (2.4 mg, 3.0 .mu.mol, Aldrich), and
N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-
-dioxaborolan-2-yl)pyridine-3-sulfonamide (12 mg, 0.030 mmol) in
THF (1.0 mL) was added Na.sub.2CO.sub.3 (7.9 mg, 0.074 mmol) in
water (0.2 mL), and the reaction was heated to 80.degree. C. for 3
hours. The reaction mixture was diluted with MeOH, filtered and
purified via preparative HPLC-MS (pH 2) to afford product as the
TFA salt (6 mg, 40%). LCMS for C.sub.18H.sub.19N.sub.8O.sub.2S
(M+H).sup.+: calculated m/z=411.1, found 411.1. .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 8.97 (d, J=2.2 Hz, 1H), 8.47 (d, J=2.3 Hz,
1H), 8.16 (s, 1H), 7.91 (s, 1H), 2.67 (s, 3H), 2.22-2.13 (m, 2H),
2.01-1.92 (m, 2H), 1.92-1.82 (m, 2H), 1.80-1.67 (m, 2H).
Example 257.
5-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-N-(4-cyanobicyc-
lo[2.1.1]hexan-1-yl)-6-methylpyridine-3-sulfonamide
##STR00399##
[1105] Prepared as in Example 256 using
3-bromo-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-8-amine (Example
472, Step 6) in Step 4 followed by purification via preparative
HPLC-MS (pH 10) to afford the title compound (6 mg, 30%). LCMS for
C.sub.20H.sub.19F.sub.3N.sub.7O.sub.2S (M+H).sup.+: calculated
m/z=478.1, found 478.2. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
9.05 (d, J=2.3 Hz, 1H), 8.27 (d, J=2.3 Hz, 1H), 7.84 (s, 1H), 7.75
(s, 1H), 2.54 (s, 3H), 2.21-2.12 (m, 2H), 2.03-1.90 (m, 2H),
1.90-1.79 (m, 2H), 1.79-1.69 (m, 2H).
Example 258.
3-(4-Amino-6-methylimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2-
.1.1]hexan-1-yl)benzenesulfonamide Trifluoroacetate Salt
##STR00400##
[1106] Step 1.
3-Bromo-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)benzenesulfonamide
##STR00401##
[1108] 1 M Na.sub.2CO.sub.3 solution (0.78 mL, 0.78 mmol) was added
to 4-aminobicyclo[2.1.1]hexane-1-carbonitrile, HCl salt (37 mg,
0.24 mmol, from 251, Step 3) in DCM (1.0 mL) and acetonitrile (0.5
mL). After 5 minutes, 3-bromobenzenesulfonyl chloride (0.028 mL,
0.196 mmol, Combi-Blocks) was added. The reaction was allowed to
warm to room temperature and was stirred overnight. The layers were
separated and the aqueous layer was extracted with two portions of
DCM. The combined organic extracts were dried over sodium sulfate,
filtered and concentrated. Flash chromatography, eluting with a
gradient from 0-100% EtOAc in hexanes and using ELSD for detection
afforded purified product (64 mg, 96%). LCMS for
C.sub.13H.sub.14BrN.sub.2O.sub.2S (M+H).sup.+: calculated
m/z=341.0, found 341.0.
Step 2.
N-(4-Cyanobicyclo[2.1.1]hexan-1-yl)-3-(4,4,5,5-tetramethyl-1,3,2-d-
ioxaborolan-2-yl)benzenesulfonamide
##STR00402##
[1110] A mixture of
3-bromo-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)benzenesulfonamide (64.0
mg, 0.188 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (61.9
mg, 0.244 mmol), potassium acetate (61 mg, 0.62 mmol) and
dichlorobis(triphenylphosphine)-palladium(II) (5.3 mg, 7.5 .mu.mol)
in THF (1.9 mL) was degassed and the mixture was heated in a
microwave at 140.degree. C. for 30 minutes. Upon cooling to room
temperature, the reaction mixture was diluted with water and EtOAc.
The layers were separated and the aqueous portion was extracted
with two further portions of EtOAc. The combined organic extracts
were washed with brine and dried over sodium sulfate, filtered and
concentrated. The product was used without further purification in
Step 3. LCMS for C.sub.19H.sub.26BN.sub.2O.sub.4S (M+H).sup.+:
calculated m/z=389.2, found 389.2.
Step 3.
3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-.sup.7-yl)-N-(4-cyanobicycl-
o[2.1.1]hexan-1-yl)benzenesulfonamide
##STR00403##
[1112] A microwave vial was charged with
N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxabor-
olan-2-yl)benzenesulfonamide (70.0 mg, 0.180 mmol),
7-bromoimidazo[2,1-f][1,2,4]triazin-4-amine (46 mg, 0.22 mmol,
Synthonix) and THF (1.8 mL), followed by the addition of 1 M aq.
K.sub.2CO.sub.3 (0.54 mL, 0.54 mmol). The reaction mixture was
degassed and heated to 90.degree. C. for 3.5 hours. Upon cooling to
room temperature, the reaction mixture was partitioned between
water and EtOAc. The aqueous layer was extracted with two further
portions of EtOAc. The combined organic extracts were dried over
sodium sulfate, filtered and concentrated. The product was purified
by flash chromatography, eluting with a gradient from 0-100% EtOAc
in hexanes to afford a white solid (68 mg, 95%). LCMS for
C.sub.18H.sub.18N.sub.7O.sub.2S (M+H).sup.+: calculated m/z=396.1,
found 396.1.
Step 4.
3-(4-Amino-6-bromoimidazo[2,1-f][1,2,4]triazin-.sup.7-yl)-N-(4-cya-
nobicyclo[2.1.1]hexan-1-yl)benzenesulfonamide
##STR00404##
[1114] A solution of
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexa-
n-1-yl)benzenesulfonamide (68 mg, 0.17 mmol) and N-bromosuccinimide
(37 mg, 0.21 mmol) in DMF (1.5 mL) was heated to 50.degree. C. for
2 hours. Upon cooling to room temperature, the reaction mixture was
diluted with EtOAc, washed with water and brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified by flash chromatography, eluting with a gradient from
0-100% EtOAc/hexanes to afford product (23 mg, 28%). LCMS for
C.sub.18H.sub.17BrN.sub.7O.sub.2S (M+H).sup.+: calculated
m/z=474.0, found 474.1.
Step 5.
3-(4-amino-6-methylimidazo[2,1-f][1,2,4]triazin-.sup.7-yl)-N-(4-cy-
anobicyclo[2.1.1]hexan-1-yl)benzenesulfonamide, Trifluoroacetate
Salt
[1115] To a degassed solution of
3-(4-amino-6-bromoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.-
1.1]hexan-1-yl)benzenesulfonamide (0.010 g, 0.021 mmol) in THF (0.5
mL) was added tetrakis(triphenylphosphine)palladium(0) (2.4 mg, 2.1
.mu.mol), followed by 2.0 M trimethylaluminum in hexanes (0.032 mL,
0.063 mmol). The reaction was sealed and heated to 100.degree. C.
for 45 minutes. Additional trimethylaluminum (2.0 M in hexanes,
0.032 mL, 0.063 mmol) was introduced, and heating was continued for
2 hours. Upon cooling to room temperature, a few drops of water
were added and MeCN was added to make the mixture monophasic. The
mixture was stirred until gas evolution subsided and then was
filtered, diluted with methanol, and the mixture was purified by
preparative HPLC-MS (pH 2) to afford product as the
trifluoroacetate salt (7.0 mg, 60%). LCMS for
C.sub.19H.sub.20N.sub.7O.sub.2S (M+H).sup.+: calculated m/z=410.1,
found 410.2. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.32-8.28
(m, 1H), 8.15 (s, 1H), 7.99-7.94 (m, 2H), 7.77 (t, J=7.9 Hz, 1H),
2.59 (s, 3H), 2.18-2.10 (m, 2H), 2.01-1.92 (m, 2H), 1.89-1.80 (m,
2H), 1.72-1.61 (m, 2H).
Example 259.
3-(4-Amino-2-cyclopropylimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-(hydroxym-
ethyl)bicyclo[2.1.1]hexan-1-yl)-4-methylbenzenesulfonamide
Trifluoroacetate Salt
##STR00405##
[1116] Step 1. 2-Cyclopropylimidazo[2,1-f][1,2,4]triazin-4-ol
##STR00406##
[1118] Dry HCl gas was bubbled through a solution of ethyl
1-amino-1H-imidazole-2-carboxylate (0.240 g, 1.55 mmol, prepared as
in US2015/0274767) and cyclopropanecarbonitrile (0.519 g, 7.73
mmol, Alfa Aesar) in dioxane (2.4 mL) for 2 minutes, during which
time the solution became a suspension, then returned to a solution.
This solution was heated in a sealed reaction vial to 110.degree.
C. for 5.5 hours. Upon cooling to room temperature, solvent was
evaporated to afford a sticky solid, which was triturated with
EtOAc and stirred overnight and the solid product was filtered off
and air dried. LCMS for C.sub.8H.sub.9N.sub.4O (M+H).sup.+:
calculated m/z=177.1, found 177.1.
Step 2. 7-Bromo-2-cyclopropylimidazo[2,1-f][1,2,4]triazin-4-ol
##STR00407##
[1120] A solution of 2-cyclopropylimidazo[2,1-f][1,2,4]triazin-4-ol
(0.330 g, 1.87 mmol, prepared as in Step 1) in DMF (10.0 mL) was
treated with NBS (0.367 g, 2.06 mmol) and the mixture was stirred
at room temperature for 2 hours. The reaction mixture was diluted
with water and sodium thiosulfate solution was added. 1 N HCl was
added to achieve pH 3 and the aqueous mixture was extracted with
four portions of EtOAc (4.times.50 mL). The combined organic
extracts were dried over sodium sulfate, filtered and concentrated
to afford a solid which was azeotroped with heptane on the rotovap
to afford an off-white solid. LCMS for C.sub.8H.sub.8BrN.sub.4O
(M+H).sup.+: calculated m/z=255.0, found 255.0.
Step 3.
7-Bromo-4-chloro-2-cyclopropylimidazo[2,1-f][1,2,4]triazine
##STR00408##
[1122] 7-Bromo-2-cyclopropylimidazo[2,1-f][1,2,4]triazin-4-ol
(0.378 g, 1.48 mmol) was heated in POCl.sub.3 (6.9 mL, 74 mmol) to
110.degree. C. overnight and the reaction was less than half
complete. N,N-dimethylaniline (0.19 mL, 1.5 mmol) and
tetraethylammonium chloride (0.491 g, 2.96 mmol) were added. The
reaction mixture was sealed and heating was continued for 2 hours,
at which point the reaction was complete. POCl.sub.3 was removed on
the rotovap and the residue was poured onto crushed ice, then the
aqueous mixture was made basic by the addition of solid
NaHCO.sub.3. The aqueous mixture was extracted with EtOAc
(3.times.). The combined organic extracts were dried over sodium
sulfate, filtered and concentrated. The product was used without
further purification. LCMS for C.sub.8H.sub.7BrClN.sub.4
(M+H).sup.+: calculated m/z=273.0, found 273.0.
Step 4.
7-Bromo-2-cyclopropylimidazo[2,1-f][1,2,4]triazin-4-amine
##STR00409##
[1124] A suspension of
7-bromo-4-chloro-2-cyclopropylimidazo[2,1-f][1,2,4]triazine (0.512
g, 1.87 mmol, prepared as in Step 3) in ammonium hydroxide (14.8 M,
13 mL, 190 mmol) was heated to 80.degree. C. for 30 minutes, then
at room temperature overnight. Brine was added and the mixture was
extracted with EtOAc (3.times.). The combined organic extracts were
dried over Na.sub.2SO.sub.4, filtered and concentrated. The product
was purified by flash chromatography, eluting with a gradient from
0-100% EtOAc in hexanes to obtain desired product as white solid
(140 mg, 29%). LCMS for C.sub.8H.sub.9BrN.sub.5 (M+H).sup.+:
calculated m/z=254.0, found 254.0. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.52 (s, 1H), 2.14 (tt, J=8.2, 4.8 Hz, 1H),
1.11 (dt, J=6.1, 3.1 Hz, 2H), 1.01 (dt, J=8.2, 3.1 Hz, 2H).
Step 5. (4-Aminobicyclo[2.1.1]hexan-1-yl)methanol Trifluoroacetate
Salt
##STR00410##
[1126] Ethyl chloroformate (0.131 mL, 1.37 mmol) was added dropwise
to a solution of
4-((tert-butoxycarbonyl)amino)bicyclo[2.1.1]hexane-1-carboxylic
acid (0.300 g, 1.24 mmol, Enamine catalog #EN300-70833) and
triethylamine (0.26 mL, 1.9 mmol) in THF (5 mL) at -5.degree. C.
The reaction was stirred for 30 minutes at this temperature. The
solid formed was filtered and washed with 2 mL THF. The pooled
washings and filtrate were cooled to 0.degree. C. and treated with
sodium borohydride (141 mg, 3.73 mmol) in one portion followed by
MeOH (2 mL), added dropwise. After 30 minutes, the reaction mixture
was quenched by the addition of water and 2N HCl. The layers were
separated, and the aqueous layer was extracted several times with
EtOAc. The combined organic extracts were dried over MgSO.sub.4,
filtered and concentrated. LCMS for C.sub.8H.sub.14NO.sub.3
(M-.sup.tBu+H).sup.+: calculated m/z=172.1, found 172.1.
[1127] tert-Butyl
(4-(hydroxymethyl)bicyclo[2.1.1]hexan-1-yl)carbamate obtained above
was dissolved in DCM (1 mL), trifluoroacetic acid (0.96 mL, 12.0
mmol) was added and reaction was stirred for 2 hours. Volatiles
were removed in vacuo to afford product as the trifluoroacetate
salt (0.15 g, 55%). LCMS for C.sub.7H.sub.14NO (M+H).sup.+:
calculated m/z=128.1, found 128.1.
Step 6.
N-(4-(Hydroxymethyl)bicyclo[2.1.1]hexan-1-yl)-4-methyl-3-(4,4,5,5--
tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide
##STR00411##
[1129] Prepared from (4-aminobicyclo[2.1.1]hexan-1-yl)methanol
Trifluoroacetate Salt analogously to the procedure for Example 249,
Steps 1 through 2. LCMS for C.sub.20H.sub.31BNO.sub.5S (M+H).sup.+:
calculated m/z=408.2, found 408.1.
Step 7.
3-(4-Amino-2-cyclopropylimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-(h-
ydroxymethyl)bicyclo[2.1.1]hexan-1-yl)-4-methylbenzenesulfonamide,
Trifluoroacetate Salt
[1130] 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride
dichloromethane complex (1.6 mg, 2.0 .mu.mol) was added to a
degassed mixture of
7-bromo-2-cyclopropylimidazo[2,1-f][1,2,4]triazin-4-amine (5.0 mg,
0.020 mmol),
N-(4-(hydroxymethyl)bicyclo[2.1.1]hexan-1-yl)-4-methyl-3-(4,4,5,5-tetrame-
thyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (8.0 mg, 0.020
mmol, from Step 6), and sodium carbonate (6.2 mg, 0.059 mmol) in
dioxane (2 mL) and water (1 mL) and the mixture was heated to
120.degree. C. for 3 hours. The reaction was diluted with MeOH and
purified via preparative HPLC-MS (pH 2) to obtain the desired
product as a white solid (1.0 mg, 9%). LCMS for
C.sub.22H.sub.27N.sub.6O.sub.3S (M+H).sup.+: calculated m/z=455.2,
found 455.1.
Example 260.
3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-N-(4-cyanobicyclo[2.-
1.1]hexan-1-yl)benzenesulfonamide Trifluoroacetate Salt
##STR00412##
[1131] Step 1.
7-(2-Chlorophenyl)imidazo[2,1-f][1,2,4]triazin-4-amine
##STR00413##
[1133] A degassed mixture of
7-bromoimidazo[2,1-f][1,2,4]triazin-4-amine (96 mg, 0.45 mmol,
Synthonix), (2-chlorophenyl)boronic acid (0.070 g, 0.45 mmol,
Aldrich) and
1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride
dichloromethane complex (37 mg, 0.045 mmol) in dioxane (2 mL) and
sodium carbonate (142 mg, 1.34 mmol) in water (1 mL) was heated to
120.degree. C. for 3 hours. Upon cooling, the reaction mixture was
diluted with water and EtOAc and the phases were separated. The
product was identified as present in the aqueous layer as a
suspension. The aqueous layer was filtered and the off white solid
was air dried (0.100 g, 91%). LCMS for C.sub.11H.sub.9ClN.sub.5
(M+H).sup.+: calculated m/z=246.1, found 246.1.
Step 2.
3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-chlorobenzenesulfon-
yl Chloride
##STR00414##
[1135] 7-(2-Chlorophenyl)imidazo[2,1-f][1,2,4]triazin-4-amine
(0.030 g, 0.12 mmol) in DCM (10 mL) and under N.sub.2 at 0.degree.
C. was treated with chlorosulfonic acid (0.081 mL, 1.22 mmol),
added dropwise. The ice bath was removed. The mixture was warmed to
room temperature and stirred for 1 hour, followed by heating to
50.degree. C. overnight. The reaction mixture was diluted with DCM
and added to stirred ice water. After the ice melted, layers were
separated and the aqueous layer was extracted with DCM (2.times.).
The combined extracts were dried over MgSO.sub.4, filtered and
concentrated. The product was purified by flash chromatography,
eluting with a gradient from 0-100%, EtOAc in Hexanes, and was
isolated as a light yellow oil (0.030 g, 71%). LCMS for
C.sub.11H.sub.8Cl.sub.2N.sub.5O.sub.2S (M+H).sup.+: calculated
m/z=344.0, found 344.0.
Step 3.
3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-.sup.7-yl)-4-chloro-N-(4-cy-
anobicyclo[2.1.1]hexan-1-yl)benzenesulfonamide
##STR00415##
[1137] To 4-aminobicyclo[2.1.1]hexane-1-carbonitrile, HCl (8.3 mg,
0.052 mmol, from Example 251, Step 3) in DCM (0.6 mL) and
acetonitrile (0.3 mL) was added 1 M Na.sub.2CO.sub.3 (0.17 mL, 0.17
mmol). The mixture was stirred for 5 minutes, then
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-chlorobenzenesulfonyl
chloride (15 mg, 0.044 mmol) was added. DMA (1 mL) was added to aid
solubility. The reaction was stirred for 2 hours. Purification via
flash chromatography, eluting with a gradient from 0-100% EtOAc in
hexanes) afforded product as colorless oil. (0.015 g, 80%). LCMS
for C.sub.18H.sub.17ClN.sub.7O.sub.2S (M+H).sup.+: calculated
m/z=430.1, found 430.1.
Step 4.
3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-.sup.7-yl)-4-cyano-N-(4-cya-
nobicyclo[2.1.1]hexan-1-yl)benzenesulfonamide, Trifluoroacetate
Salt
[1138] A degassed mixture of
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-chloro-N-(4-cyanobicyclo[2-
.1.1]hexan-1-yl)benzenesulfonamide (15 mg, 0.035 mmol),
tris(dibenzylideneacetone)dipalladium(0) (1.6 mg, 1.7 .mu.mol),
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (1.4 mg, 3.5
.mu.mol), and zinc cyanide (8.2 mg, 0.070 mmol) in a mixture of DMF
(2 mL) and water (20 .mu.L) was heated in microwave at 150.degree.
C. for 30 minutes. The crude reaction mixture was filtered and
purified via preparative HPLC-MS (pH 2) to afford product as a
white solid (5.0 mg, 27%). LCMS for C.sub.19H.sub.17N.sub.8O.sub.2S
(M+H).sup.+: calculated m/z=421.1, found 421.1. .sup.1H NMR (600
MHz, DMSO-d.sub.6) .delta. 9.09 (s, 1H), 8.52 (s, 1H), 8.49 (d,
J=1.7 Hz, 1H), 8.43 (s, 1H), 8.28 (d, J=8.3 Hz, 1H), 8.19 (s, 1H),
8.14 (s, 1H), 8.02 (dd, J=8.2, 1.9 Hz, 1H), 2.07-1.99 (m, 2H),
1.93-1.87 (m, 2H), 1.76-1.70 (m, 2H), 1.69-1.63 (m, 2H).
Example 261.
3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexa-
n-1-yl)-N-methyl-4-(methyl-d.sub.3)benzenesulfonamide
##STR00416##
[1139] Step 1. 4-(Methylamino)bicyclo[2.1.1]hexane-1-carbonitrile,
Hydrochloric Acid Salt
##STR00417##
[1141] Sodium hydride (60% in mineral oil, 1.2 mg, 0.049 mmol) was
added to a mixture of tert-butyl
(4-cyanobicyclo[2.1.1]hexan-1-yl)carbamate (0.010 g, 0.045 mmol,
prepared as in Example 251, Step 2) in DMF (1 mL) at 0.degree. C.
After the reaction mixture was stirred for 5 minutes, it was
treated with methyl iodide (3 .mu.L, 0.05 mmol). After stirring for
2 hours at 0.degree. C., water was added and the mixture was
extracted with EtOAc. The organic extract was washed with brine,
dried over MgSO.sub.4, filtered and concentrated. The crude product
was treated with HCl (4M in dioxane) (0.5 mL, 2 mmol) and was
stirred for 1 hour. Volatiles were removed in vacuo and the product
was used without further purification in Step 2. Theoretical yield
was assumed. LCMS for C.sub.8H.sub.13N.sub.2(M+H).sup.+: calculated
m/z=137.1, found 137.2.
Step 2.
3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-.sup.7-yl)-N-(4-cyanobicycl-
o[2.1.1]hexan-1-yl)-N-methyl-4-(methyl-d.sub.3)benzenesulfonamide
[1142] To 4-(methylamino)bicyclo[2.1.1]hexane-1-carbonitrile, HCl
(5 mg, 0.03 mmol, from Step 1) in DCM (0.6 mL) was added Hunig's
base (5 .mu.L, 0.03 mmol) and the mixture was cooled to 0.degree.
C. After stirring for 5 minutes,
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-(methyl-d.sub.3)benzenesul-
fonyl chloride (7.6 mg, 0.023 mmol, Example 253, Step 3) in 0.5 mL
DMA was added. The mixture was allowed to warm to room temperature
over 30 minutes, and the product was purified by preparative
HPLC-MS (pH 10) to afford a white solid (4.0 mg, 30%). LCMS for
C.sub.20H.sub.19D.sub.3N.sub.7O.sub.2S (M+H).sup.+: calculated
m/z=427.2, found 427.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
8.34 (s, 1H), 8.25 (s, 1H), 8.09 (s, 1H), 7.97 (d, J=2.0 Hz, 1H),
7.85 (s, 1H), 7.80 (dd, J=8.1, 2.0 Hz, 1H), 7.64 (d, J=8.1 Hz, 1H),
2.82 (s, 3H), 2.19-2.07 (m, 2H), 2.02-1.85 (m, 4H), 1.71-1.54 (m,
2H).
[1143] The following Examples provided in Tables 9-19 were prepared
according to Method A or Method B, unless otherwise noted.
TABLE-US-00009 TABLE 9 ##STR00418## LCMS Ex. Name -N(R).sub.2 [M +
H].sup.+ No. NMR Spectra 262.sup.A
3-(8-Amino-6-methylimidazo[1,2-a]pyrazin-3-yl)-N-(4-
(hydroxymethyl)bicyclo[2.1.1]hexan-1-yl)-4-
methylbenzenesulfonamide ##STR00419## 428.1 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 7.95 (dd, J = 8.1, 1.8 Hz, 1H), 7.85 (d, J =
1.7 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.61 (s, 1H), 7.06 (s, 1H),
3.54 (s, 2H), 2.28 (s, 3H), 2.25 (s, 3H), 1.82- 1.71 (m, 2H),
1.59-1.51 (m, 2H), 1.51-1.42 (m, 2H), 1.26-1.13 (m, 2H) 263.sup.A
3-(8-Amino-6-methylimidazo[1,2-a]pyrazin-3-yl)-N-(4-
cyanobicyclo[2.1.1]hexan-1-yl)-4- methylbenzenesulfonamide
trifluoroacetate salt ##STR00420## 423.2 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.77 (s, 1H), 7.94-7.91 (m, 2H), 7.78 (d, J =
1.6 Hz, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.25 (s, 1H), 2.25 (s, 6H),
2.02-1.93 (m, 2H), 1.93-1.84 (m, 2H), 1.74-1.66 (m, 2H), 1.66-1.53
(m, 2H) 264.sup.B
3-(8-Amino-6-methylimidazo[1,2-a]pyrazin-3-yl)-N-(3-
cyanobicyclo[1.1.1]pentan-1-yl)-4- methylbenzenesulfonamide
trifluoroacetate salt ##STR00421## 409.1
TABLE-US-00010 TABLE 10 ##STR00422## LCMS Ex. Name -N(R).sub.2 [M +
H].sup.+ No. NMR Spectra 265.sup.B
3-(4-Amino-2-methylimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(4-
cyanobicyclo[2.1.1]hexan-1-yl)-4-methylbenzenesulfonamide
trifluoroacetate salt ##STR00423## 424.1 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.71 (s, 1H), 8.40 (s, 1H), 8.28 (s, 1H),
7.95 (d, J = 1.9 Hz, 1H), 7.81 (dd, J = 8.1, 2.0 Hz, 1H), 7.79 (s,
1H), 7.62 (d, J = 8.2 Hz, 1H), 2.36 (s, 3H), 2.30 (s, 3H),
2.02-1.93 (m, 2H), 1.93-1.84 (m, 2H), 1.74-1.68 (m, 2H), 1.64-1.56
(m, 2H) 266.sup.A
3-(4-Amino-2-methylimidazo[1,2-f][1,2,4]triazin-7-yl)-4-
methyl-N-(3,3,3-trifluoro-2-hydroxypropyl) benzenesulfonamide
(single enantiomer isolated) ##STR00424## 431.1 .sup.1H NMR (600
MHz, DMSO-d.sub.6) .delta. 8.21 (s, 1H), 8.13 (s, 1H), 7.91 (d, J =
2.0 Hz, 1H), 7.79 (dd, J = 8.1, 2.0 Hz, 1H), 7.73 (s, 1H), 7.62 (d,
J = 8.2 Hz, 1H), 6.63 (br s, 1H), 4.10-3.96 (m, 1H), 3.06 (dd, J =
13.6, 4.1 Hz, 1H), 2.90 (dd, J = 13.6, 7.9 Hz, 1H), 2.34 (s, 3H),
2.27 (s, 3H). 267.sup.A
3-(4-Amino-2-methylimidazo[1,2-f][1,2,4]triazin-7-yl)-4-
methyl-N-(3,3,3-trifluoro-2- hydroxypropyl)benzenesulfonamide
(single enantiomer isolated) ##STR00425## 431.1 .sup.1H NMR
(400MHz, DMSO-d.sub.6) .delta. 8.27 (s, 1H), 8.18 (s, 1H), 7.98 (t,
J = 6.1 Hz, 1H), 7.91 (d, J = 1.3 Hz, 1H), 7.80 (dd, J = 7.8, 1.2
Hz, 1H), 7.75 (s, 1H), 7.62 (d, J = 8.2 Hz, 1H), 6.60 (br s, 1H),
3.12-2.99 (m, 1H), 2.95-2.86 (m, 1H), 2.34 (s, 3H), 2.28 (s, 3H)
268.sup.A
3-(4-Amino-2-methylimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(4-
(hydroxymethyl)bicyclo[2.1.1]hexan-1-yl)-4-
methylbenzenesulfonamide trifluoroacetate salt ##STR00426## 429.2
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.33 (s, 1H), 8.28 (s,
1H), 8.19 (s, 1H), 7.93 (d, J = 1.6 Hz, 1H), 7.79 (dd, J = 8.0, 1.7
Hz, 1H), 7.74 (s, 1H), 7.59 (d, J = 8.1 Hz, 1H), 3.35 (s, 2H), 2.34
(s, 3H), 2.28 (d, J = 4.8 Hz, 3H), 1.76-1.59 (m, 2H), 1.44-1.39 (m,
2H), 1.38-1.28 (m, 2H), 1.12-0.97 (m, 2H) 269.sup.A
3-(4-Amino-2-methylimidazo[1,2-f][1,2,4]triazin-7-yl)-N-((1-
hydroxycyclobutyl)methyl)-4-methylbenzenesulfonamide
trifluoroacetate salt ##STR00427## 403.1 .sup.1H NMR (600 MHz,
DMSO-d.sub.6) .delta. 8.28 (s, 1H), 8.18 (s, 1H), 7.92 (d, J = 2.0
Hz, 1H), 7.81 (dd, J = 8.0, 2.0 Hz, 1H), 7.74 (s, 1H), 7.60 (d, J =
8.1 Hz, 1H), 7.53 (t, J = 6.4 Hz, 1H), 2.83 (d, J = 6.4 Hz, 2H),
2.32 (s, 3H), 2.29 (s, 3H), 2.04-1.95 (m, 2H), 1.92-1.82 (m, 2H),
1.65-1.55 (m, 1H), 1.45-1.35 (m, 1H). 270.sup.B
3-(4-Amino-2-methylimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(3-
cyanobicyclo[1.1.1]pentan-1-yl)-4-methylbenzenesulfonamide
trifluoroacetate salt ##STR00428## 410.2 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.94 (s, 1H), 8.27 (s, 1H), 8.19 (s, 1H),
7.94-7.89 (m, 1H), 7.81- 7.71 (m, 2H), 7.64 (d, , J = 8.0 Hz, 1H),
2.37 (s, 3H), 2.29 (s, 9H) 271.sup.A
3-(4-amino-2-methylimidazo[1,2-f][1,2,4]triazin-7-yl)-N-
((1r,4r)-4-hydroxy-4-methylcyclohexyl)-4- methylbenzenesulfonamide
trifluoroacetate salt ##STR00429## 431.1 272.sup.A
3-(4-amino-2-methylimidazo[1,2-f][1,2,4]triazin-7-yl)-N-
((1r,3r)-3-cyanocyclobutyl)-4-methylbenzenesulfonamide
trifluoroacetate salt ##STR00430## 398.1 273.sup.A
3-(4-amino-2-methylimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(2-
hydroxy-2-methylpropyl)-4-methylbenzenesulfonamide trifluoroacetate
salt ##STR00431## 391.1 .sup.1H NMR (600 MHz, DMSO) .delta. 8.50
(s, 1H), 8.36 (s, 1H), 7.89 (d, J = 2.0 Hz, 1H), 7.79 (dd, J = 8.0,
2.0 Hz, 1H), 7.78 (s, 1H), 7.60 (d, J = 8.2 Hz, 1H), 2.67 (d, J =
6.6 Hz, 2H), 2.33 (s, 3H), 2.30 (s, 3H), 1.07 (s, 6H).
TABLE-US-00011 TABLE 11 ##STR00432## Ex. LCMS No. Name -N(R).sub.2
[M + H].sup.+ NMR Spectra 274.sup.B
3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-
N-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-4-
methylbenzenesulfonamide trifluoroacetate salt ##STR00433## 468.1
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.96 (dd, J = 8.1, 1.9
Hz, 1H), 7.87 (d, J = 1.8 Hz, 1H), 7.76 (s, 1H), 7.69 (d, J = 8.2
Hz, 1H), 7.59 (s, 1H), 3.54 (s, 2H), 2.30 (s, 3H), 1.75 (s, 6H).
275.sup.B
3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-
N-(4-(hydroxymethyl)bicyclo[hexan-l-yl)-4- methylbenzenesulfonamide
trifluoroacetate salt ##STR00434## 482.1 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 7.98 (dd, J = 8.1, 1.9 Hz, 1H), 7.89 (d, J =
1.8 Hz, 1H), 7.77 (s, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.58 (s, 1H),
3.54 (s, 2H), 2.30 (s, 3H), 1.83-1.69 (m, 2H), 1.61-1.53 (m, 2H),
1.52-1.42 (m, 2H), 1.28-1.11 (m, 2H) 276.sup.B
3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-
N-(3-(cyanomethyl)bicyclo[1.1.1]pentan-1-yl)-4-
methylbenzenesulfonamide trifluoroacetate salt ##STR00435## 477.1
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.71 (s, 1H), 7.87 (dd,
J = 8 1, 1.9 Hz, 1H), 7.82 (s, 1H), 7.81 (d, J = 1.8 Hz, 1H), 7.70
(br s, 2H), 7.69 (d, J = 8.2 Hz, 1H), 7.59 (s, 1H), 2.79 (s, 2H),
2.28 (s, 3H), 1.73 (s, 6H) 277.sup.B Methyl
3-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2- a]pyrazin-3-yl)-4-
methylphenylsulfonamido)bicyclo[1.1.1]pentane-1- carboxylate
trifluoroacetate salt ##STR00436## 496.1 278.sup.B
3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-
N-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-4-
methylbenzenesulfonamide trifluoroacetate salt ##STR00437## 488.2
279.sup.B
3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-
4-methyl-N-(3-(oxazol-5-yl)bicyclo[1.1.1]pentan-1-
yl)benzenesulfonamide trifluoroacetate salt ##STR00438## 505.2
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.07 (s, 1H), 7.99 (dd, J
= 8.1, 2.0 Hz, 1H), 7.90 (d, J = 1.9 Hz, 1H), 7.78 (s, 1H), 7.71
(d, J = 8.1 Hz, 1H), 7.59 (s, 1H), 6.86 (s, 1H), 5.51 (s, 1H), 2.31
(s, 3H), 2.19 (s, 6H) 280.sup.B
N-(3-((1H-1,2,4-triazol-1-yl)methyl)bicyclo[1.1.1]pentan-1-
yl)-3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-
yl)-4-methylbenzenesulfonamide ##STR00439## 519.2 .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 8.39 (s, 1H), 7.90 (s, 1H), 7.82 (dd, J
= 8.0, 1.9 Hz, 1H), 7.80 (s, 1H), 7.76 (d, J = 1.7 Hz, 1H), 7.71
(s, 2H), 7.65 (d, J = 8.1 Hz, 1H), 7.56 (s, 1H), 4.29 (s, 2H), 2.26
(s, 3H), 1.61 (s, 6H) 281.sup.B
3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-
N-(4-cyanobicyclo[2.1.1]hexan-l-yl)-4- methylbenzenesulfonamide
trifluoroacetate salt ##STR00440## 477.2 282.sup.B
3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-
N-(3-(2-hydroxypropan-2-yl)bicyclo[1.1.1]pentan-l-yl)-4-
methylbenzenesulfonamide trifluoroacetate salt ##STR00441## 496.2
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.00-7.93 (m, 1H),
7.90-7.83 (m, 1H), 7.77 (s, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.58 (s,
1H), 2.30 (s, 3H), 1.73 (s, 6H), 1.10 (s, 6H) 283.sup.B
N-(3-((1H-pyrazol-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)
(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-
methylbenzenesulfonamide trifluoroacetate salt ##STR00442## 518.2
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.62 (s, 1H), 7.83 (dd,
J = 8.1, 1.9 Hz, 1H), 7.80 (s, 1H), 7.77 (d, J = 1.8 Hz, 1H), 7.71
(br s, 2H), 7.67 (d, J = 8.1 Hz, 1H), 7.58-7.50 (m, 2H), 7.37 (d, J
= 1.4 Hz, 1H), 6.18 (t, J = 2.0 Hz, 1H), 4.19 (s, 2H), 2.26 (s,
3H), 1.59 (s, 6H) 284.sup.B
N-(3-((1H-imidazol-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)-
3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-
4-methylbenzenesulfonamide trifluoroacetate salt ##STR00443## 518.1
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.02 (t, J = 1.4 Hz,
1H), 8.74 (s, 1H), 7.85 (dd, J = 8.0, 1.9 Hz, 1H), 7.81 (s, 1H),
7.79 (d, J = 1.8 Hz, 1H), 7.72 (br s, 2H), 7.69 (d, J = 1.9 Hz,
1H), 7.68-7.65 (m, 2H), 7.63 (t, J = 1.5 Hz, 1H), 7.57 (s, 1H),
7.39 (d, J = 8.0 Hz, 1H), 4.35 (s, 2H), 2.27 (s, 3H), 1.68 (s, 6H)
285.sup.B
3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-
N-(3-fluorobicyclo[1.1.1]pentan-1-yl)-4- methylbenzenesulfonamide
trifluoroacetate salt ##STR00444## 456.1 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.84 (s, 1H), 7.87 (dd, J = 8.1, 1.9 Hz, 1H),
7.83 (s, 1H), 7.81 (d, J = 1.7 Hz, 1H), 7.74-7.65 (m, 2H), 7.59 (s,
1H), 2.27 (s, 3H), 2.09 (d, J = 2.0 Hz, 6H) 286.sup.B
3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-
N-(3-(fluoromethyl)bicyclo[1.1.1]pentan-l-yl)-4-
methylbenzenesulfonamide trifluoroacetate salt ##STR00445## 470.1
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.96 (dd, J = 8.1, 2.0
Hz, 1H), 7.87 (d, J = 2.0 Hz, 1H), 7.76 (s, 1H), 7.69 (d, J = 8.2
Hz, 1H), 7.58 (s, 1H), 4.37 (d, J = 47.7 Hz, 1H), 2.31 (s, 3H),
1.84 (s, 6H) 287.sup.B
3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-
N-(3-cyanobicyclo[1.1.1]pentan-1-yl)-4- methylbenzenesulfonamide
##STR00446## 463.2 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.85
(dd, J = 8.1, 1.9 Hz, 1H), 7.83 (s, 1H), 7.79 (d, J = 1.7 Hz, 1H),
7.70 (br s, 2H), 7.68 (d, J = 8.3 Hz, 1H), 7.61 (s, 1H), 2.26 (s,
3H), 2.25 (s, 6H) 288.sup.B
3-(3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-
yl)-4-methylphenylsulfonamido)bicyclo[1.1.1]pentane-1- carboxamide
trifluoroacetate salt ##STR00447## 481.2 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.69 (s, 1H), 7.87 (dd, J = 8.0, 2.0 Hz, 1H),
7.83 (s, 1H), 7.81 (d, J = 1.8 Hz, 1H), 7.70 (br s, 2H), 7.70 (d, J
= 8.1 Hz, 1H), 7.60 (s, 1H), 7.17 (s, 1H), 6.91 (s, 1H), 2.27 (s,
3H), 1.88 (s, 6H) 289.sup.B
3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-
4-methyl-N-(3-(morpholinomethyl)bicyclo[1.1.1]pentan-1-
yl)benzenesulfonamide trifluoroacetate salt ##STR00448## 537.1
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.97 (dd, J = 8.1, 1.8
Hz, 1H), 7.87 (d, J = 1.7 Hz, 1H), 7.75 (s, 1H), 7.69 (d, J = 8.2
Hz, 1H), 7.59 (s, 1H), 4.14 - 3.06 (br m, 8H), 3.37 (s, 2H), 2.31
(s, 3H), 2.05 (s, 6H) 290.sup.B
3-(3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-
yl)-4-methylphenylsulfonamido)bicyclo[1.1.1]pentane-1- carboxylic
acid trifluoroacetate salt ##STR00449## 482.1 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 7.97 (dd, J = 8.0, 1.8 Hz, 1H), 7.87 (d, J =
1.5 Hz, 1H), 7.76 (s, 1H), 7.70 (d, J = 8.2 Hz, 1H), 7.59 (s, 1H),
2.31 (s, 3H), 2.09 (s, 6H) 291.sup.B
4-(3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-
yl)-4-methylphenylsulfonamido)bicyclo[2.1.1]hexane-1- carboxamide
trifluoroacetate salt ##STR00450## 495.1 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.48 (s, 1H), 7.88 (dd, J = 8 1, 1.9 Hz, 1H),
7.85-7.81 (m, 2H), 7.71 (br s, 2H), 7.68 (d, J = 8.2 Hz, 1H), 7.59
(s, 1H), 7.06 (s, 1H), 6.84 (s, 1H), 2.28 (s, 3H), 1.76-1.57 (m,
6H), 1.39-1.25 (m, 2H) 292.sup.B
N-(3-(1H-Tetrazol-5-yl)bicyclo[1.1.1]pentan-1-yl)-3-(8-
amino-6-(trifluoromethyl)imidazo[l,2-a]pyrazin-3-yl)-4-
methylbenzenesulfonamide trifluoroacetate salt ##STR00451## 506.3
.sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. 8.75 (br, 1H), 7.91
(dd, J = 8.0, 2.0 Hz, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.83 (s, 1H),
7.71 (d, J = 8.1 Hz, 1H), 7.70 (br s, 2H), 7.61 (s, 1H), 6.52 (s,
1H), 2.28 (s, 3H), 2.04 (s, 6H) 293.sup.B
3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-
4-methyl-N-(3-(3-methyl-1,2,4-oxadiazol-5-
yl)bicyclo[1.1.1]pentan-1-yl)benzenesulfonamide trifluoroacetate
salt ##STR00452## 520.0 .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta.
8.96 (s, 1H), 7.91 (dd, J = 8 1, 2.0 Hz, 1H), 7.85 (d, J = 2.0 Hz,
1H), 7.83 (s, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.69 (br s, 2H), 7.60
(s, 1H), 2.28 (s, 3H), 2.27 (s, 3H), 2.24 (s, 6H) 294.sup.B
3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-
4-methyl-N-(3-(1-methyl-1H-imidazol-2-
yl)bicyclo[1.1.1]pentan-1-yl)benzenesulfonamide trifluoroacetate
salt ##STR00453## 518.1 .sup.1H NMR (400 MHz, CD.sub.3OD).delta.
8.01 (dd, J = 8.1, 1.9 Hz, 1H), 7.91 (d, J = 1.9 Hz, 1H), 7.76 (s,
1H), 7.72 (d, J = 8.2 Hz, 1H), 7.59 (s, 1H), 7.45 (d, J = 1.9 Hz,
1H), 7.42 (d, J = 1.9 Hz, 1H), 3.82 (s, 3H), 2.51 (s, 6H), 2.31 (s,
3H) 295.sup.B
N-(3-(1,2,4-Oxadiazol-5-yl)bicyclo[1.1.1]pentan-1-yl)-3-(8-
amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-
methylbenzenesulfonamide trifluoroacetate salt ##STR00454## 506.0
296.sup.B
3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-
4-methyl-N-(3-morpholinobicyclo[1.1.1]pentan-1-
yl)benzenesulfonamide trifluoroacetate salt ##STR00455## 523.1
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.98 (dd, J = 8.1, 2.0
Hz, 1H), 7.88 (d, J = 2.0 Hz, 1H), 7.76 (s, 1H), 7.71 (d, J = 8.2
Hz, 1H), 7.59 (s, 1H), 3.95-3.80 (m, 4H), 3.03-2.95 (m, 4H), 2.30
(s, 3H), 2.15 (s, 6H) 297.sup.B
2-((3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-
yl)-4-methylphenypsulfonyl)-2-azaspiro[3.3]heptan-6-ol ##STR00456##
468.2 298.sup.B
4-((3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-
yl)-4-methylphenypsulfonyl)-1-methylpiperazin-2-one ##STR00457##
469.2 299.sup.B 3-(8-amino-6-(trifluoromethyl)imidazo
[1,2-a]pyrazin-3-yl)-
N-((3S,4S)-4-hydroxy-1-methylpyrrolidin-3-yl)-N,4-
dimethylbenzenesulfonamide ##STR00458## 485.2 300.sup.B
3-(5-((2-(3,5-dimethylisoxazol-4-yl)pyrrolidin-1-
yl)sulfonyl)-2-methylphenyl)-6- (trifluoromethyflimidazo
[1,2-a]pyrazin-8-amine ##STR00459## 521.1 301.sup.B
3-(8-amino-6-(trifluoromethyl)imidazo [1,2-a]pyrazin-3-yl)-
N-(2-cyanoethyl)-N-cyclohexyl-4- methylbenzenesulfonamide
##STR00460## 507.1 302.sup.B
3-((3-(8-amino-6-(trifluoromethyl)imidazo [1,2-a]pyrazin-3-
yl)-4-methylphenypsulfonyl)-3-azabicyclo[3.1.0]hexane-1-
carbonitrile ##STR00461## 463.2 303.sup.B
2-((3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-
yl)-4-methylphenypsulfonyl)-2,5-diazabicyclo[2.2.1]heptan- 7-o1
2HC1 ##STR00462## 469.2 304.sup.B 3-(5-((hexahydropyrrolo
[3,4-b][1,4]oxazin-4(4aH)- yl)sulfonyl)-2-methylphenyl)-6-
(trifluoromethyflimidazo [1,2-a]pyrazin-8-amine ##STR00463## 483.1
305.sup.Ex.464 (S)-3-(5-((3-aminopyrrolidin-1-yl)sulfonyl)-2-
methylphenyl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-8- amine
bis(trifluoroacetate) ##STR00464## 441.1 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.13-7.93 (m, 3H), 7.89-7.78
(m, 3H), 7.76-7.70 (m, 2H), 7.67 (s, 2H), 3.83-3.56 (m, 1H),
3.48-3.36 (m, 1H), 3.32 (dd, J = 10.7, 6.6 Hz, 1H), 3.24-3.08 (m,
2H), 2.29 (s, 3H), 2.17-1.99 (m, 1H), 1.95 1.73 (m, 1H).
306.sup.Ex.464
3-(5-(((3R,5S)-3-amino-5-methylpiperidin-1-yl)sulfonyl)-2-
methylphenyl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-8- amine
##STR00465## 469.2 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
8.06-7.43 (m, 7H), 3.66 (d, J = 6.9 Hz, 1H), 3.56 (d, J = 7.9 Hz,
1H), 2.75-2.56 (m, 1H), 2.28 (s, 3H), 1.84-1.69 (m, 3H), 1.69-1.36
(m, 3H), 0.81 (d, J = 6.5 Hz, 3H), 0.58 (dd, J = 11.8 Hz, 1H).
307.sup.Ex.464
3-(5-(((3R,5S)-3-amino-5-(trifluoromethyl)piperidin-1-
yl)sulfonyl)-2-methylphenyl)-6-
(trifluoromethyl)imidazo[1,2-a]pyrazin-8-amine ##STR00466## 523.1
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.09-7.39 (m, 7H), 3.80
(d, J = 9.8 Hz, 1H), 3.76- 3.57 (m, 1H), 2.89-2.60 (m, 2H),
2.40-2.10 (m, 4H), 2.08-1.85 (m, 2H), 1.85-1.41 (m, 2H), 1.17-0.77
(m, 1H). 308.sup.Ex.464
3-(5-(((3S,4R)-3-amino-4-fluoropiperidin-1-yl)sulfonyl)-2-
methylphenyl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-8- amine
##STR00467## 473.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
8.17-7.21 (m, 7H), 4.64 (d, J = 49.5 Hz, 1H), 3.48- 3.33 (m, 2H),
2.98-2.73 (m, 1H), 2.58-2.49 (m, 1H), 2.39-2.30 (m, 1H), 2.28 (s,
3H), 2.08-1.62 (m, 4H). 309.sup.Ex.464
(R)-3-(5-((3-(dimethylamino)piperidin-1-yl)sulfonyl)-2-
methylphenyl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-8- amine
##STR00468## 483.2 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
8.04-7.33 (m, 7H), 3.55 (d, J = 9.9 Hz, 1H), 3.43 (d, J = 10.9 Hz,
1H), 2.42-2.30 (m, 3H), 2.28 (s, 3H), 2.15 (s, 6H) 1.81-1.63 (m,
2H), 1.54- 1.38 (m, 1H), 1.32-1.12 (m, 1H). 310.sup.A
3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-
N-(trans-4-hydroxycyclohexyl)-4- methylbenzenesulfonamide
##STR00469## 470.1 .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. 7.85
(dd, J = 8.0, 2.0 Hz, 1H), 7.81 (d, J = 2.4 Hz, 2H), 7.69 (br s,
2H), 7.67-7.62 (m, 2H), 7.57 (d, J = 0.9 Hz, 1H), 4.48 (d, J = 4.2
Hz, 1H), 3.32-3.23 (m, 1H), 3.00-2.85 (m, 1H), 2.25 (s, 3H), 1.70
(br d, J = 9.7 Hz, 2H), 1.61 (br d, J = 10.6 Hz, 2H), 1.22-1.13 (m,
2H), 1.13-1.02 (m, 2H). 311.sup.A
3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-
N-(3S,6R)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-4-
methylbenzenesulfonamide ##STR00470## 486.2 .sup.1H NMR (600 MHz,
DMSO-d.sub.6) .delta. 7.87 (dd, J = 8.1, 2.1 Hz, 1H), 7.82 (d, J =
2.2 Hz, 1H), 7.82 (s, 1 H) 7.69 (br s, 2H), 7.67 (d, J = 8.2 Hz,
1H), 7.62 (s, 1H), 4.56 (br s, 1H), 3.80- 3.60 (m, 1H), 3.37-3.25
(m, 1H), 3.25-3.18 (m, 1H), 3.16-3.07 (m, 1H), 3.05-2.93 (m, 2H),
2.26 (s, 3H), 1.72-1.65 (m, 1H), 1.63-1.52 (m, 1H), 1.40-1.25 (m,
1H), 1.20- 1.06 (m, 1H). 312.sup.B
(1-((3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-
3-yl)-4-methylphenypsulfonyl)-3-methylpiperidin-3- yl)methanol
##STR00471## 484.1 313.sup.B
3-(5((3-Methoxypiperidin-1-yl)sulfonyl)-2-methylphenyl)-
6-(trifluoromethyl)imidazo[1,2-a]pyrazin-8-amine ##STR00472## 470.1
314.sup.B
1-((3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-
yl)-4-methylphenypsulfonyl)piperidine-3-carbonitrile ##STR00473##
465.1
TABLE-US-00012 TABLE 12 ##STR00474## LCMS Ex. Name -N(R).sub.2 [M +
H].sup.+ No. NMR Spectra 315.sup.B
3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-
7-yl)-N-((3-fluorooxetan-3-yl)methyl)-4- methylbenzenesulfonamide
trifluoroacetate salt ##STR00475## 461.1 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.98 (s, 1H), 8.94 (s, 1H), 8.18 (t, J = 6.5
Hz, 1H), 7.96 (s, 1H), 7.95 (d, J = 1.9 Hz, 1H), 7.85 (dd, J = 8.1,
1.9 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 4.58 (q, J = 8.3 Hz, 2H),
4.53 (q, J = 8.3 Hz, 2H), 3.34 (dd, J = 21.9, 6.5 Hz, 2H), 2.35 (s,
3H) 316.sup.A
3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-
7-yl)-N-((3-hydroxyoxetan-3-yl)methyl)-4- methylbenzenesulfonamide
trifluoroacetate salt ##STR00476## 459.1 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.97 (s, 1H), 8.93 (s, 1H), 7.95 (s, 1H),
7.94 (d, J = 2.0 Hz, 1H), 7.86 (dd, J = 8.1, 2.0 Hz, 1H), 7.82 (t,
J = 6.5 Hz, 1H), 7.65 (d, J = 8.2 Hz, 1H), 4.37 (d, J = 10.3 Hz,
2H), 4.36 (d, J = 10.2 Hz, 2H), 3.03 (d, J = 6.5 Hz, 2H), 2.34 (s,
3H) 317.sup.A
3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-
7-yl)-N-(2-hydroxy-2-methylpropyl)-4- methylbenzenesulfonamide
trifluoroacetate salt ##STR00477## 445.2 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.97 (s, 1H), 8.93 (s, 1H), 7.94 (s, 1H),
7.91 (d, J = 1.8 Hz, 1H), 7.83 (dd, J = 8.1, 1.9 Hz, 1H), 7.63 (d,
J = 8.1 Hz, 1H), 7.50 (t, J = 6.5 Hz, 1H), 2.66 (d, J = 6.6 Hz,
2H), 2.33 (s, 3H), 1.06 (s, 6H) 318.sup.A
3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-
7-yl)-4-methyl-N-((3-methyloxetan-3- yl)methyl)benzenesulfonamide
trifluoroacetate salt ##STR00478## 457.1 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.98 (s, 1H), 8.93 (s, 1H), 7.96 (s, 1H),
7.94 (d, J = 2.0 Hz, 1H), 7.90-7.81 (m, 2H), 7.66 (d, J = 8.1 Hz,
1H), 4.32 (d, J = 5.8 Hz, 2H), 4.16 (d, J = 5..9 Hz, 2H), 2.97 (d,
J = 6.6 Hz, 2H), 2.36 (s, 3H), 1.19 (s, 3H) 319.sup.B
3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-
7-yl)-N-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-4-
methylbenzenesulfonamide ##STR00479## 469.0 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.96 (s, 1H), 8.92 (s, 1H), 8.53 (s, 1H),
7.92 (s, 1H), 7.90 (d, J = 2.0 Hz, 1H), 7.82 (dd, J = 8.1, 2.0 Hz,
1H), 7.64 (d, J = 8.2 Hz, 1H), 3.33 (s, 2H), 2.34 (s, 3H), 1.59 (s,
6H) 320.sup.A
3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-
7-yl)-N-((1S,3R)-3-cyanocyclopentyl)-4- methylbenzenesulfonamide
(single enantiomer isolated) ##STR00480## 466.1 321.sup.A
3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-
7-yl)-N-((1S,3R)-3-cyanocyclopentyl)-4- methylbenzenesulfonamide
(single enantiomer isolated) ##STR00481## 466.1 322.sup.A
3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-
7-yl)-4-methyl-N-(1-methylazetidin-3- yl)benzenesulfonamide
##STR00482## 442.1 .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.97
(s, 1H), 8.92 (s, 1H), 8.16 (d, J = 8.3 Hz, 1H), 7.93 (s, 1H), 7.88
(d, J = 2.0 Hz, 1H), 7.80 (dd, J = 8.1, 2.0 Hz, 1H), 7.63 (d, J =
8.2 Hz, 1H), 3.76-3.66 (m, 1H), 3.30-3.27 (m, 2H), 2.64-2.58 (m,
2H), 2.33 (s, 3H), 2.10 (s, 3H). 323.sup.A
3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-
7-yl)-N-((1r,3r)-3-(hydroxymethyl)cyclobutyl)-4-
methylbenzenesulfonamide trifluoroacetate salt ##STR00483## 457.2
.sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. 8.97 (s, 1H), 8.93 (s,
1H), 7.96 (d, J = 8.5 Hz, 1H), 7.93 (s, 1H), 7.87 (d, J = 1.7 Hz,
1H), 7.79 (dd, J = 8.0, 1.7 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 3.72
(h, J = 8.0 Hz, 1H), 3.30 (d, J = 6.7 Hz, 2H), 2.32 (s, 3H), 2.08
(dp, J = 12.6, 6.5 Hz, 1H), 1.88-1.76 (m, 4H). .sup.19F NMR (565
MHz, DMSO-d6) .delta. -69.03 (s), -74.61 (s). 324.sup.B
N-(3-((1H-Imidazol-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)-
3-(4-amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-7-
yl)-4-methylbenzenesulfonamide trifluoroacetate salt ##STR00484##
519.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.02 (s, 1H),
8.98 (s, 1H), 8.94 (s, 1H), 8.71 (s, 1H), 7.93 (s, 1H), 7.90 (d, J
= 1.9 Hz, 1H), 7.80 (dd, J = 8.1, 1.9 Hz, 1H), 7.72-7.56 (m, 3H),
4.34 (s, 2H), 2.34 (s, 3H), 1.68 (s, 6H) 325.sup.A
N-((1-Acetyl-3-hydroxyazetidin-3-yl)methyl)-3-(4-amino-2-
(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-7-yl)-4-
methylbenzenesulfonamide trifluoroacetate salt ##STR00485## 500.1
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.97 (s, 1H), 8.93 (s,
1H), 7.98-7.80 (m, 4H), 7.65 (d, J = 8.1 Hz, 1H), 5.89 (br s, 1H),
4.03 (d, J = 8.7 Hz, 1H), 3.87-3.78 (m, 2H), 3.55 (d, J = 9.9 Hz,
1H), 2.95 (d, J = 6.3 Hz, 2H), 2.34 (s, 3H), 1.74 (s, 3H) 326.sup.B
3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-
7-yl)-N-(2-hydroxy-2-methylpropyl)-4- methylbenzenesulfonamide
trifluoroacetate salt ##STR00486## 459.1 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.97 (s, 1H), 8.93 (s, 1H), 7.94 (s, 1H),
7.92 (d, J = 1.8 Hz, 1H), 7.84 (dd, J = 8.1, 1.9 Hz, 1H), 7.63 (d,
J = 8.2 Hz, 1H), 7.56 (t, J = 6.6 Hz, 1H), 3.02 (s, 3H), 2.77 (d, J
= 6.6 Hz, 2H), 2.33 (s, 3H), 1.05 (s, 6H) 327.sup.A
3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-
7-yl)-N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)-4-
methylbenzenesulfonamide trifluoroacetate salt ##STR00487## 485.2
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.96 (s, 1H), 8.92 (s,
1H), 7.93 (s, 1H), 7.92 (d, J = 1.9 Hz, 1H), 7.83 (dd, J = 8.1, 2.0
Hz, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.58 (d, J = 6.9 Hz, 1H),
3.20-2.94 (m, 1H), 2.33 (s, 3H), 1.69-1.54 (m, 2H), 1.55-1.36 (m,
2H), 1.34-1.16 (m, 4H), 1.05 (s, 3H). .sup.19F NMR (376 MHz,
DMSO-d6) .delta. -69.04 (s), -74.58 (s). 328.sup.A
3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-
7-yl)-N-(4-(hydroxymethyl)bicyclo[2.1.1]hexan-1-yl)-4-
methylbenzenesulfonamide trifluoroacetate salt ##STR00488## 483.1
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.97 (d, J = 1.7 Hz, 1H),
7.92 (dd, J = 8.1, 1.9 Hz, 1H), 7.82 (s, 1H), 7.60 (d, J = 8.1 Hz,
1H), 3.53 (s, 2H), 2.36 (s, 3H), 1.84-1.69 (m, 2H), 1.58 - 1.51 (m,
2H), 1.51-1.38 (m, 2H), 1.26-1.16 (m, 2H) 329.sup.A
3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-
7-yl)-N-(1-(2-hydroxyethyl)azetidin-3-yl)-4-
methylbenzenesulfonamide trifluoroacetate salt ##STR00489## 472.1
330.sup.B
3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-
7-yl)-N-(3-cyanobicyclo[1.1.1]pentan-1-yl)-4-
methylbenzenesulfonamide trifluoroacetate salt ##STR00490## 464.1
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.98 (d, J = 1.6 Hz, 1H),
7.89 (dd, J = 7.9, 1.6 Hz, 1H), 7.85 (s, 1H), 7.65 (d, J = 8.3 Hz,
1H), 2.41 (s, 3H), 2.31 (s, 6H). 331.sup.B
3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-
7-yl)-N-(3-(fluoromethyl)bicyclo[1.1.1]pentan-1-yl)-4-
methylbenzenesulfonamide trifluoroacetate salt ##STR00491## 471.1
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.96 (d, J = 1.9 Hz, 1H),
7.90 (dd, J = 8.1, 2.0 Hz, 1H), 7.83 (s, 1H), 7.62 (d, J = 8.2 Hz,
1H), 4.35 (d, J = 47.7 Hz, 1H), 2.38 (s, 3H), 1.82 (s, 6H)
332.sup.B
N-(3-((1H-pyrazol-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)-3-
(4-amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-7-
yl)-4-methylbenzenesulfonamide trifluoroacetate salt ##STR00492##
519.2 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.98 (s, 1H),
8.93 (s, 1H), 8.58 (s, 1H), 7.90 (s, 1H), 7.87 (d, J = 1.8 Hz, 1H),
7.78 (dd, J = 8.1, 1.9 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.55 (d,
J = 2.0 Hz, 1H), 7.36 (d, J = 1.4 Hz, 1H), 6.18 (t, J = 2.0 Hz,
1H), 4.18 (s, 2H), 2.33 (s, 3H), 1.59 (s, 6H) 333.sup.B
3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-
7-yl)-N-(3-fluorobicyclo[1.1.1]pentan-1-yl)-4-
methylbenzenesulfonamide trifluoroacetate salt ##STR00493## 457.1
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.97 (s, 1H), 8.92 (s,
1H), 8.80 (s, 1H), 7.95 (s, 1H), 7.92 (d, J = 1.9 Hz, 1H), 7.82
(dd, J = 8.1, 2.0 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 2.36 (s, 3H),
2.08 (d, J = 2.4 Hz, 6H) 334.sup.A
3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-
7-yl)-N-((4-(hydroxymethyl)tetrahydro-2H-pyran-4-
yl)methyl)-4-methylbenzenesulfonamide trifluoroacetate salt
##STR00494## 501.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.97
(s, 1H), 8.93 (s, 1H), 7.95 (s, 1H), 7.93-7.88 (m, 1H), 7.87-7.79
(m, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.45 (t, J = 6.5 Hz, 1H),
3.63-3.37 (m, 4H), 3.29 (s, 2H), 2.79 (d, J = 6.7 Hz, 2H), 2.34 (s,
3H), 1.39-1.26 (m, 4H) 335.sup.A
3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-
7-yl)-N-((3-hydroxyazetidin-3-yl)methyl)-4-
methylbenzenesulfonamide trifluoroacetate salt ##STR00495## 458.1
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.99 (s, 1H), 8.96 (s,
1H), 8.80 (br s, 1H), 8.66 (br s, 1H), 8.00 (t, J = 6.8 Hz, 1H),
7.95 (s, 1H), 7.93 (d, J = 1.4 Hz, 1H), 7.86 (dd, J = 8.0, 1.8 Hz,
1H), 7.67 (d, J = 8.0 Hz, 1H), 6.26 (s, 1H), 3.99-3.86 (m, 2H),
3.84-3.69 (m, 2H), 3.01 (d, J = 6.5 Hz, 2H), 2.34 (s, 3H) 336.sup.B
3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-
-NH.sub.2 373.1 7-yl)-4-methylbenzenesulfonamide trifluoroacetate
salt .sup.1H NMR (400 MHz, DMSO-d.sub.6 containing CD.sub.3OD)
.delta. 7.90 (d, J = 1.8 Hz, 1H), 7.86 (dd, J = 7.7, 2.2 Hz, 1H),
7.86 (s, 1H), 7.59 (d, J = 8.1 Hz, 1H), 2.26 (s, 3H) 337.sup.A
3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-
7-yl)-4-methyl-N-(1-(oxetan-3-yl)azetidin-3-yl) benzenesulfonamide
trifluoroacetate salt ##STR00496## 484.1 338.sup.B
N-(3-((1H-1,2,4-triazol-1-yl)methyl)bicyclo[1.1.1]pentan-1-
yl)-3-(4-amino-2-(trifluoromethyl)imidazo[1,2-
f][1,2,4]triazin-7-yl)-4-methylbenzenesulfonamide ##STR00497##
520.2 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.94 (br s, 2H),
8.38 (s, 1H) 7.91 (s, 1H), 7.90 (s, 1H), 7.88 (d, J = 1.9 Hz, 1H),
7.78 (dd, J = 8.1, 1.9 Hz, 1H), 7.62 (d, J = 8.2 Hz, 1H), 4.28 (s,
2H), 2.34 (s, 3H), 1.62 (s, 6H) 339.sup.B
3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-
7-yl)-N-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-4-
methylbenzenesulfonamide trifluoroacetate salt ##STR00498## 489.1
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.97 (d, J = 2.0 Hz, 1H),
7.90 (dd, J = 8.1, 2.0 Hz, 1H), 7.83 (s, 1H), 7.63 (d, J = 8.1 Hz,
1H), 5.81 (t, J = 56.4 Hz, 1H), 2.38 (s, 3H), 1.91 (s, 6H)
340.sup.B
3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-
7-yl)-4-methyl-N-(3-morpholinobicyclo[1.1.1]pentan-1-
yl)benzenesulfonamide trifluoroacetate salt ##STR00499## 524.1
341.sup.B
3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-
7-yl)-N-(3-aminobicyclo[1.1.1]pentan-1-yl)-4-
methylbenzenesulfonamide trifluoroacetate salt ##STR00500##
454.1
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.97 (d, J = 2.0 Hz, 1H),
7.91 (dd, J = 8.1, 2.0 Hz, 1H), 7.83 (s, 1H), 7.64 (d, J = 8.1 Hz,
1H), 2.38 (s, 3H), 2.15 (s, 6H) 342.sup.B
1-((3-(4-amino-2-(trifluoromethyl)imidazo[2,1-f]
[1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)-3-
cyclopropylazetidin-3-ol TFA ##STR00501## 469.1 343.sup.B
2-((3-(4-amino-2-(trifluoromethyl)imidazo[2,1-f]
[1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)-2-
azaspiro[3.3]heptan-6-ol TFA ##STR00502## 469.1 344.sup.B
3-(4-amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-
yl)-N-(2-cyanoethyl)-N,4-dimethylbenzenesulfonamide ##STR00503##
440.2 345.sup.B
3-(4-amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-
7-yl)-N-(2-cyanoethyl)-N-cyclopropyl-4- methylbenzenesulfonamide
##STR00504## 466.2 346.sup.B
3-(4-amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-
7-yl)-N-(2-cyanoethyl)-N-cyclopentyl-4- methylbenzenesulfonamide
##STR00505## 494.2 347.sup.B
(S)-(1-((3-(4-amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]
triazin-7-yl)-4-methylphenyl)sulfonyl)pyrrolidin-2-yl)methanol
##STR00506## 457.2 348.sup.B
2-((3-(4-amino-2-(trifluoromethyl)imidazo[2,1-f]
[1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)-6-methyl-
2,6-diazaspiro[3.4]octan-5-one ##STR00507## 496.2 349.sup.B
2-((3-(4-amino-2-(trifluoromethyl)imidazo[2,1-f]
[1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)-5-ethyl-2,5-
diazabicyclo[2.2.1]heptan-7-ol ##STR00508## 498.2 350.sup.B
2-((3-(4-amino-2-(trifluoromethyl)imidazo[2,1-f]
[1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)-5-isopropyl-
2,5-diazabicyclo[2.2.1]heptan-7-ol ##STR00509## 512.2 351.sup.B
3-(5-((3-(4-amino-2-(trifluoromethyl)imidazo[2,1-f]
[1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)-7-hydroxy-
2,5-diazabicyclo[2.2.1]heptan-2-yl)cyclopentane-1-carbonitrile
##STR00510## 563.2 352.sup.B
2-((3-(4-amino-2-(trifluoromethyl)imidazo[2,1-f]
[1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)-5-methyl-
2,5-diazabicyclo[2.2.1]heptan-7-ol ##STR00511## 484.2 353.sup.B
2-(5-((3-(4-amino-2-(trifluoromethyl)imidazo[2,1-f]
[1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)-7-hydroxy-
2,5-diazabicyclo[2.2.1]heptan-2-yl)cyclopentane-1-carbonitrile
##STR00512## 563.2 354.sup.B
3-(5-((3-(4-amino-2-(trifluoromethyl)imidazo[2,1-f]
[1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)-7-hydroxy-
2,5-diazabicyclo[2.2.1]heptan-2-yl)cyclobutane-1- carbonitrile
##STR00513## 549.2 355.sup.B
2-((3-(4-amino-2-(trifluoromethyl)imidazo[2,1-f]
[1,2,4]triazin-7-yl)-4-methylphenyl)sulfonyl)-2,5-
diazabicyclo[2.2.1]heptan-7-ol ##STR00514## 470.1 356.sup.A
3-(4-amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-
7-yl)-N-((3S,6R)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)-4-methylbenzenesulfonamide ##STR00515## 487.1 .sup.1H NMR (400
MHz, DMSO) .delta. 8.70 (br s, 2H), 7.97-7.85 (m, 2H), 7.82 (dd, J
= 8.1, 1.9 Hz, 1H), 7.62 (d, J = 8.2 Hz, 1H), 4.66-4.41 (m, 1H),
3.77-3.55 (m, 1H), 3.28-3.23 (m, 1H), 3.24-3.15 (m, 1H), 3.15-3.06
(m, 1H), 3.03-2.92 (m, 2H), 2.32 (s, 3H), 1.75-1.62 (m, 1H),
1.62-1.47 (m, 1H), 1.40-1.20 (m, 1H), 1.20-1.00 (m, 1H). 357.sup.B
3-(4-amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-
7-yl)-4-methyl-N-((1-methyl-1H-pyrazol-5-
yl)methyl)benzenesulfonamide ##STR00516## 467.2 358.sup.B
3-(4-amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-
7-yl)-4-methyl-N-(pyrazin-2-ylmethyl)benzenesulfonamide
##STR00517## 465.1
TABLE-US-00013 TABLE 13 ##STR00518## LCMS Ex. Name -N(R).sub.2 R' =
[M +H].sup.+ No. .sup.1H NMR 359.sup.A
5-(8-aminoimidazo[1,2-a]pyrazin-3-yl)-2-fluoro-N-
((1r,4r-4-hydroxy-4- methylcyclohexypbenzenesulfonamide
##STR00519## 4-F 420.2 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
8.00 (s, 1H), 7.98-7.90 (m, 2H), 7.79 (s, 1H), 7.68 (d, J = 4.6 Hz,
1H), 7.61 (dd, J = 9.5 Hz, 1H), 7.30 (d, J = 4.7 Hz, 1H), 7.01 (s,
2H), 4.13 (s, 1H), 3.27-3.19 (m, 1H), 1.68-1.56 (m, 2H), 1.55-1.43
(m, 2H), 1.38-1.19 (m, 4H), 1.05 (s, 3H). 360.sup.A
5-(8-aminoimidazo[1,2-a]pyrazin-3-yl)-2-fluoro-N-
((4-(hydroxymethyl)tetrahydro-2H-pyran-4-
yl)methyl)benzenesulfonamide ##STR00520## 4-F 436.1 .sup.1H NMR
(600 MHz, DMSO-d.sub.6) .delta. 7.99-7.92 (m, 2H), 7.79 (s, 1H),
7.71 (d, J = 4.7 Hz, 1H), 7.66-7.59 (m, 1H), 7.30 (d, J = 4.7 Hz,
1H), 7.02 (s, 2H), 3.48 (dd, J = 5.5, 5.5 Hz, 4H), 3.29 (s, 2H),
2.95 (s, 2H), 1.42-1.26 (m, 4H). 361.sup.A
5-(8-aminoimidazo[1,2-a]pyrazin-3-yl)-N-(2-
hydroxy-2-methylpropyl)-2,4- dimethylbenzenesulfonamide
##STR00521## 2,4- diMe 390.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 7.72 (s, 1H), 7.63 (s 1H), 7.54 (br s, 1H), 7.46 (s, 1H),
7.26-7.17 (m, 2H), 6.99 (s, 2H), 4.36 (s, 1H), 2.71 (s, 2H), 2.62
(s, 3H), 2.18 (s, 3H), 1.02 (s, 6H).
TABLE-US-00014 TABLE 14 ##STR00522## LCMS Ex. Name --N(R).sub.2 R'
= [M + H].sup.+ No. NMR Spectra 362.sup.B
3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-
cyanobicyclo[2.2.1]heptan-1-yl)-4-(methyl-
d.sub.3)benzenesulfonamide trifluoroacetate salt ##STR00523##
2-CD.sub.3 427.2 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.13 (s,
1H), 8.03 (d, J = 2.0 Hz, 1H), 7.90 (dd, J = 8.1, 2.1 Hz, 1H), 7.80
(s, 1H), 7.61 (d, J = 8.1 Hz, 1H), 2.05-1.95 (m, 2H), 1.94 (s, 2H),
1.90-1.76 (m, 4H), 1.70-1.57 (m, 2H) 363.sup.A
5-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(4-
(hydroxymethyl)bicyclo[2.1.1]hexan-1-yl)-2,4-
dimethylbenzenesulfonamide ##STR00524## 2-CH.sub.3, 4-CH.sub.3
429.1 .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.08 (s, 1H), 8.06
(s, 1H), 7.70 (s, 1H), 7.40 (s, 1H) 3.53 (s, 2H), 2.70 (s, 3H),
2.34 (s, 3H), 1.80-1.72 (m, 2H), 1.57-1.51 (m, 2H), 1.51-1.39 (m,
2H), 1.27-1.17 (m, 2H) 364.sup.A
3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(4-
cyanobicyclo[2.1.1]hexan-1-yl)benzenesulfonamide trifluoroacetate
salt ##STR00525## -- 396.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 8.80 (s, 1H), 8.71-8.64 (m, 1H), 8.38 (s, 1H), 8.37-8.29
(m, 1H), 8.31 (s, 1H), 8.23 (s, 1H), 8.18 (s, 1H), 7.87-7.80 (m,
1H), 7.74 (t, J = 7.8 Hz, 1H), 2.05-1.96 (m, 2H), 1.92-1.84 (m,
2H), 1.77-1.69 (m, 2H), 1.65-1.58 (m, 2H) 365.sup.A
5-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(4-
cyanobicyclo[2.1.1]hexan-1-yl)-2- fluorobenzenesulfonamide
trifluoroacetate salt ##STR00526## 4-F 414.1 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.11 (s, 1H), 8.68 (dd, J = 7.0, 2.1 Hz, H),
8.40-8.33 (m, 2H), 8.30 (s, 1H), 8.22 (s, 1H), 8.17 (s, 1H),
7.66-7.56 (m, 1H), 2.09-2.01 (m, 2H), 1.93- 1.85 (m, 2H), 1.78-1.71
(m, 2H), 1.71-1.64 (m, 2H) 366.sup.A
5-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-2-
fluoro-N-(4-(hydroxymethyl)bicyclo[2.1.1]hexan-1-
yl)benzenesulfonamide trifluoroacetate salt ##STR00527## 4-F 419.2
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.72 (s, 1H), 8.66 (dd,
J = 6.9, 2.0 Hz, H), 8.41-8.33 (m, 2H), 8.31 (s, 1H), 8.22 (s, 1H),
8.15 (s, 1H), 7.59 (t, J = 9.4 Hz, 1H), 3.33 (s, 2H), 1.74-1.66 (m,
2H), 1.51-1.44 (m, 2H), 1.40-1.31 (m, 2H), 1.12-1.04 (m, 2H)
367.sup.A 5-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-2-
chloro-N-(4-(hydroxymethyl)bicyclo[2.1.1]hexan-1-
yl)benzenesulfonamide trifluoroacetate salt ##STR00528## 4-Cl 435.1
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.87 (d, J = 2.1 Hz,
1H), 8.64 (s, 1H), 8.37 (s, 1H), 8.34- 8.27 (m, 2H), 8.22 (s, 1H),
8.19 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 3.32 (s, 2H), 1.75-1.67 (m,
2H), 1.50-1.43 (m, 2H), 1.37-1.28 (m, 2H), 1.11-1.02 (m, 2H)
368.sup.A 3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(4-
(hydroxymethyl)bicyclo[2.1.1]hexan-1- yl)benzenesulfonamide
trifluoroacetate salt ##STR00529## -- 401.1 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.75 (s, 1H), 8.32 (d, J = 7.7 Hz, 1H), 8.20
(s, 1H), 8.06 (s, 1H), 7.92 (d, J = 7.7 Hz, 1H), 7.70 (t, J = 7.9
Hz, 1H), 3.52 (s, 2H), 1.86-1.77 (m, 2H), 1.61- 1.53 (m, 2H),
1.51-1.43 (m, 2H), 1.27-1.19 (m, 2H) 369.sup.B
5-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(4-
cyanobicyclo[2.1.1]hexan-1-yl)-2- methylbenzenesulfonamide
trifluoroacetate salt ##STR00530## 4-CH.sub.3 410.1 .sup.1H NMR
(600 MHz, DMSO-d.sub.6) .delta. 8.81 (s, 1H), 8.71 (d, J = 1.7 Hz,
1H), 8.34 (s, 1H), 8.27 (s, 1H), 8.20 (s, 1H), 8.17 (dd, J = 7.9,
1.8 Hz, 1H), 8.12 (s, 1H), 7.55 (d, J = 8.1 Hz, 1H), 2.64 (s, 2H),
2.07-1.98 (m, 2H), 1.91-1.84 (m, 2H), 1.78-1.68 (m, 2H), 1.68-1.60
(m, 2H) 370.sup.B 3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-
((1r,3r)-3-cyanocyclobutyl)-4-(methyl- d.sub.3)benzenesulfonamide
trifluoroacetate salt ##STR00531## 2-CD.sub.3 387.1 .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 8.18 (s, 1H), 8.00 (d, J = 1.9 Hz,
1H), 7.86 (dd, J = 8.1, 2.0 Hz, 1H), 7.81 (s, 1H), 7.62 (d, J = 8.1
Hz, 1H), 4.13 (p, J = 7.7 Hz, 1H), 3.09 (ttd, J = 9.7, 3.7, 1.5 Hz,
1H), 2.54-2.43 (m, 2H), 2.35-2.22 (m, 2H) 371.sup.B
3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(3-
(isocyanomethyl)bicyclo[1.1.1]pentan-1-yl)-4-
(methyl-d.sub.3)benzenesulfonamide trifluoroacetate salt
##STR00532## 2-CD.sub.3 413.2 .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 8.14 (s, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.88 (dd, J = 8.1,
2.0 Hz, 1H), 7.79 (s, 1H), 7.62 (d, J = 8.1 Hz, 1H), 2.73 (s, 2H),
1.88 (s, 6H) 372.sup.A
3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(4-
cyanobicyclo[2.1.1]hexan-1-yl)-4- methoxybenzenesulfonamide
trifluoroacetate salt ##STR00533## 2-OMe 426.1 .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 8.66 (d, J = 2.4 Hz, 1H), 8.18 (s, 1H),
8.04 (s, 1H), 7.95 (dd, J = 8.9, 2.4 Hz, 1H), 7.37 (d, J = 8.8 Hz,
1H), 4.03 (s, 3H), 2.21-2.09 (m, 2H), 1.99-1.90 (m, 2H), 1.90-1.77
(m, 2H), 1.73-1.58 (m, 2H) 373.sup.A
3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(4-
cyanobicyclo[2.1.1]hexan-1-yl)-4-
(trifluoromethoxy)benzenesulfonamide trifluoroacetate salt
##STR00534## 2- OCF.sub.3 480.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 8.93 (s, 1H), 8.54 (d, J = 2.0 Hz, 1H), 8.43 (s, 1H), 8.37
(s, 1H), 8.17 (s, 1H), 8.01 (dd, J = 8.6, 1.8 Hz, 1H), 7.93 (s,
1H), 7.81 (d, J = 8.7 Hz, 1H), 2.09- 1.96 (m, 2H), 1.96-1.84 (m,
2H), 1.81-1.69 (m, 2H), 1.69-1.59 (m, 2H) 374.sup.B
3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-
hydroxybicyclo[2.1.1]hexan-1-yl)-4-(methyl-
d.sub.3)benzenesulfonamide ##STR00535## 2-CD.sub.3 404.2 .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. 8.08 (s, 1H), 8.00 (d, J = 1.9
Hz, 1H), 7.88 (dd, J = 8.1, 2.1 Hz, 1H), 7.74 (s, 1H), 7.59 (d, J =
8.1 Hz, 1H), 4.59 (s, 1H), 1.81-1.70 (m, 2H), 1.66-1.55 (m, 4H),
1.55-1.49 (m, 2H) 375.sup.A
3-(4-aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-5-
fluoro-N-(1-(hydroxymethyl)-2- oxabicyclo[2.2.2]octan-4-yl)-4-
methylbenzenesulfonamide trifluoroacetate salt ##STR00536##
2-CH.sub.3 3-F 463.1 376.sup.A
5-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-2-
fluoro-N-((1r,4r)-4-hydroxy-4- methylcyclohexyl)benzenesulfonamide
##STR00537## 4-F 421.2 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
8.64 (dd, J = 6.9, 2.1 Hz, 1H), 8.39-8.22 (m, 3H), 8.19 (s, 1H),
8.13 (s, 1H), 7.98 (br s, 1H), 7.57 (dd, J = 9.4, 9.4 Hz, 1H), 4.12
(s, 1H), 3.25-3.12 (m, 1H), 1.68-1.56 (m, 2H), 1.54-1.43 (m, 2H),
1.39-1.18 (m, 4H), 1.04 (s, 3H). 377.sup.A
5-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-2-
chloro-N-((1r,4r)-4-hydroxy-4- methylcyclohexyl)benzenesulfonamide
##STR00538## 4-Cl 437.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
8.85 (d, J = 2.0 Hz, 1H), 8.41-8.24 (m, 3H), 8.19 (d, J = 7.3 Hz,
2H), 7.88 (br s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 4.11 (s, 1H),
3.21-3.06 (m, 1H), 1.66- 1.56 (m, 2H), 1.55-1.44 (m, 2H), 1.43-1.29
(m, 2H), 1.29-1.13 (m, 2H), 1.05 (s, 3H).
TABLE-US-00015 TABLE 15 ##STR00539## LCMS Ex. Name --N(R).sub.2 R'
= [M + H].sup.+ No. NMR Spectra 378.sup.B
3-(8-Amino-6-methylimidazo[1,2-a]pyrazin-3-yl)-N-
(3-(isocyanomethyl)bicyclo[1.1.1]pentan-1-yl)-4-
(methyl-d.sub.3)benzenesulfonamide trifluoroacetate salt
##STR00540## 2-CD.sub.3 426.2 .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 7.98 (dd, J = 8.1, 2.0 Hz, 1H), 7.86 (d, J = 1.9 Hz, 1H),
7.82 (s, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.22-7.16 (m, 1H), 2.73 (s,
2H), 2.34 (d, J = 0.9 Hz, 3H), 1.88 (s, 6H) 379.sup.B
3-(8-Amino-6-methylimidazo[1,2-a]pyrazin-3-yl)-N-
(4-cyanobicyclo[2.1.1]hexan-1-yl)-4-(methyl-
d.sub.3)benzenesulfonamide trifluoroacetate salt ##STR00541##
2-CD.sub.3 426.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.76
(s, 1H), 7.91 (dd, J = 8.1, 2.0 Hz, 1H), 7.86 (s, 1H), 7.78 (d, J =
2.0 Hz, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.21 (s, 1H), 2.23 (s, 3H),
2.02-1.93 (m, 2H), 1.93-1.81 (m, 2H), 1.74-1.65 (m, 2H), 1.65-1.54
(m, 2H) 380.sup.A 5-(8-Amino-6-methylimidazo[1,2-a]pyrazin-3-yl)-N-
(4-cyanobicyclo[2.1.1]hexan-1-yl)-2- fluorobenzenesulfonamide
trifluoroacetate salt ##STR00542## 4-F 427.1 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.20 (s, 1H), 8.07 (s, 1H), 8.04-7.96 (m,
2H), 7.77- 7.65 (m, 2H), 2.29 (s, 3H), 2.08-1.98 (m, 2H), 1.93-1.84
(m, 2H), 1.74-1.68 (m, 2H), 1.68-1.60 (m, 2H) 381.sup.A
3-(8-Amino-6-methylimidazo[1,2-a]pyrazin-3-yl)-N-
(4-(hydroxymethyl)bicyclo[2.1.1]hexan-1- yl)benzenesulfonamide
##STR00543## -- 414.1 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
8.11 (t, J = 1.4 Hz, 1H), 8.03-7.94 (m, 1H), 7.93-7.84 (m, 1H),
7.77 (t, J = 7.8 Hz, 1H), 7.74 (s, 1H), 7.61 (s, 1H), 3.53 (s, 2H),
2.31 (s, 3H), 1.85- 1.66 (m, 2H), 1.66-1.53 (m, 2H), 1.53-1.42 (m,
2H), 1.28-1.14 (m, 2H) 382.sup.B
5-(8-Amino-6-methylimidazo[1,2-a]pyrazin-3-yl)-N-
(3-cyanobicyclo[1.1.1]pentan-1-yl)-2- fluorobenzenesulfonamide
trifluoroacetate salt ##STR00544## 4-F 413.1 .sup.1H NMR (600 MHz,
DMSO-d.sub.6) .delta. 9.44 (s, 1H), 8.06-7.89 (m, 3H), 7.70 (t, J =
9.3 Hz, 1H), 7.65 (s, 1H), 2.29 (s, 6H), 2.27 (s, 3H) 383.sup.B
3-(8-Amino-6-methylimidazo[1,2-a]pyrazin-3-yl)-N-
(4-(hydroxymethyl)bicyclo[2.1.1]hexan-1-yl)-4-
(methyl-d.sub.3)benzenesulfonamide trifluoroacetate salt
##STR00545## 2-CD.sub.3 431.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 9.02 (s, 1H), 8.40 (s, 1H), 7.90 (dd, J = 8.3, 2.1 Hz, 1H),
7.89 (s, 1H), 7.77 (d, J = 1.8 Hz, 1H), 7.68 (d, J = 8.1 Hz, 1H),
7.19 (s, 1H), 3.35 (s, 2H), 2.24 (s, 3H), 1.76-1.58 (m, 2H),
1.45-1.38 (m, 2H), 1.38-1.32 (m, 2H), 1.08-0.99 (m, 2H) 384.sup.B
3-(8-Amino-6-methylimidazo[1,2-a]pyrazin-3-yl)-N-
(4-hydroxybicyclo[2.1.1]hexan-1-yl)-4-(methyl-
d.sub.3)benzenesulfonamide ##STR00546## 2-CD.sub.3 417.2 385.sup.A
5-(8-amino-6-methylimidazo[1,2-a]pyrazin-3-yl)-2-
chloro-N-((1r,4r)-4-hydroxy-4- methylcyclohexyl)benzenesulfonamide
##STR00547## 4-Cl 450.1 .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta.
8.12 (d, J = 2.2 Hz, 1H), 7.93 (s, 1H), 7.89 (dd, J = 8.2, 2.2 Hz,
1H), 7.79 (d, J = 8.2 Hz, 1H), 7.78 (s, 1H), 7.58 (d, J = 0.9 Hz,
1H), 7.00 (s, 2H), 4.13 (s, 1H), 3.25-3.14 (m, 1H), 2.20 (s, 3H),
1.66-1.57 (m, 2H), 1.55-1.47 (m, 2H), 1.40-1.30 (m, 2H), 1.29-1.23
(m, 2H), 1.05 (s, 3H).
TABLE-US-00016 TABLE 16 ##STR00548## LCMS Ex. Name --N(R).sub.2 R'
= [M + H].sup.+ No. NMR Spectra 386.sup.B
3-(4-Amino-2-methylimidazo[2,1-f][1,2,4]triazin-7-
yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-4-(methyl-
d.sub.3)benzenesulfonamide trifluoroacetate salt ##STR00549##
2-CD.sub.3 427.3 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.70
(s, 1H), 8.24 (s, 1H), 8.16 (s, 1H), 7.95 (d, J = 1.9 Hz, 1H), 7.80
(dd, J = 8.1, 2.1 Hz, 1H), 7.76 (s, 1H), 7.62 (d, J = 8.1 Hz, 1H),
2.29 (s, 3H), 2.02- 1.93 (m, 2H), 1.93-1.84 (m, 2H), 1.77-1.67 (m,
2H), 1.61 (m, 2H) 387.sup.A
5-(4-Amino-2-methylimidazo[1,2-f][1,2,4]triazin-7-
yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-2- fluorobenzenesulfonamide
trifluoroacetate salt ##STR00550## 4-F 428.1 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.13 (s, 1H), 8.72 (dd, J = 7.1, 2.1 Hz, 1H),
8.35 (ddd, J = 8.1, 4.2, 2.0 Hz, 1H), 8.26 (s, 1H), 8.20 (s, 1H),
8.10 (s, 1H), 7.61 (t, J = 9.4 Hz, 1H), 2.39 (s, 3H), 2.11-1.99 (m,
2H), 1.93-1.79 (m, 2H), 1.79-1.69 (m, 2H), 1.69-1.58 (m, 2H)
388.sup.B 5-(4-Amino-2-methylimidazo[1,2-f][1,2,4]triazin-7-
yl)-N-(3-cyanobicyclo[1.1.1]pentan-1-yl)-2-
fluorobenzenesulfonamide trifluoroacetate salt ##STR00551## 4-F
414.1 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.74 (dd, J = 6.9,
2.1 Hz, 1H), 8.32 (ddd, J = 8.2, 4.5, 2.2 Hz, 1H), 7.97 (s, 1H),
7.48 (t, J = 9.3 Hz, 1H), 2.50 (s, 3H), 2.37 (s, 6H) 389.sup.A
5-(4-amino-2-methylimidazo[2,1-f][1,2,4]triazin-7-
yl)-2-chloro-N-((3S,6R)-6-(cyanomethyl)tetrahydro-
2H-pyran-3-yl)-4-methylbenzenesulfonamide ##STR00552## 2-Me, 4-Cl
476.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.29-7.96 (m,
4H), 7.77 (s, 1H), 7.73 (s, 1H), 3.72 (d, J = 8.2 Hz, 1H),
3.49-3.38 (m, 1H), 3.20-3.00 (m, 2H), 2.77-2.63 (m, 1H), 2.57 (dd,
J = 17.1, 6.5 Hz, 1H), 2.34 (s, 3H), 2.27 (s, 3H), 1.81-1.71 (m,
1H), 1.71-1.60 (m, 1H), 1.59- 1.36 (m, 1H), 1.35-1.14 (m, 1H).
TABLE-US-00017 TABLE 17 ##STR00553## LCMS Ex. Name --N(R).sub.2 R'
= [M + H].sup.+ No. NMR Spectra 390.sup.B
3-(8-Amino-6-(trifluoromethyl)imidazo[1,2- a]pyrazin-3-yl)-N-(4-
(hydroxymethyl)bicyclo[2.1.1]hexan-1-yl)-4-
(methyl-d.sub.3)benzenesulfonamide trifluoroacetate salt
##STR00554## 2-CD.sub.3 485.1 .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 7.98 (dd, J = 8.1, 2.0 Hz, 1H), 7.89 (d, J = 2.0 Hz, 1H),
7.77 (s, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.58 (s, 1H), 3.54 (s, 2H),
1.81-1.71 (m, 2H), 1.61-1.52 (m, 2H), 1.52-1.43 (m, 2H), 1.27-1.15
(m, 2H) 391.sup.B 3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-
a]pyrazin-3-yl)-N-(3- (hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-4-
(methyl-d.sub.3)benzenesulfonamide trifluoroacetate salt
##STR00555## 2-CD.sub.3 471.1 .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 7.96 (dd, J = 8.1, 2.0 Hz, 1H), 7.87 (d, J = 1.9 Hz, 1H),
7.77 (s, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.59 (s, 1H), 3.54 (s, 2H),
1.75 (s, 6H) 392.sup.A 5-(8-Amino-6-(trifluoromethyl)imidazo[1,2-
a]pyrazin-3-yl)-2-chloro-N-(4- cyanobicyclo[2.1.1]hexan-1-
yl)benzenesulfonamide trifluoroacetate salt ##STR00556## 4-Cl 497.1
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.34 (d, J = 2.0 Hz, 1H),
8.08 (s, 1H), 7.91 (dd, J = 8.2, 2.1 Hz, 1H), 7.89 (s, 1H), 7.84
(d, J = 8.3 Hz, 1H), 2.16-2.06 (m, 2H), 2.01-1.90 (m, 2H),
1.88-1.79 (m, 2H), 1.75-1.67 (m, 2H) 393.sup.B
3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-
a]pyrazin-3-yl)-4-chloro-N-(4-
(hydroxymethyl)bicyclo[2.1.1]hexan-1- yl)benzenesulfonamide
##STR00557## 2-Cl 502.1 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
8.08-8.01 (m, 2H), 7.89 (d, 1H), 7.82 (s, 1H), 7.69 (s, 1H), 3.55
(s, 2H), 1.85-1.72 (m, 2H), 1.62-1.56 (m, 2H), 1.54-1.48 (m, 2H),
1.29-1.19 (m, 2H) 394.sup.A
3-(8-Amino-6-(trifluoromethyl)imidazo[1,2- a]pyrazin-3-yl)-N-(4-
(hydroxymethyl)bicyclo[2.1.1]hexan-1- yl)benzenesulfonamide
trifluoroacetate salt ##STR00558## -- 468.1 395.sup.A
3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-
a]pyrazin-3-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-
yl)benzenesulfonamide trifluoroacetate salt ##STR00559## -- 463.1
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.87 (s, 1H), 8.10-8.06
(m, 1H), 8.04 (s, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.96-7.91 (m, 2H),
7.81 (t, J = 7.8 Hz, 1H), 7.70 (s, 2H), 2.04-1.94 (m, 2H),
1.92-1.84 (m, 2H), 1.75-1.67 (m, 2H), 1.66-1.56 (m, 2H) 396.sup.A
5-(8-Amino-6-(trifluoromethyl)imidazo[1,2-
a]pyrazin-3-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-
yl)-2-fluorobenzenesulfonamide trifluoroacetate salt ##STR00560##
4-F 481.1 .sup.1H NMR (400 MHz ,CD.sub.3OD) .delta. 8.14 (dd, J =
6.7, 2.1 Hz, 1H), 8.04 (s, 1H), 8.01-7.92 (m, 1H), 7.85 (s, 1H),
7.58 (t, J = 9.3 Hz, 1H), 2.19-2.10 (m, 2H), 2.02-1.93 (m, 2H),
1.89- 1.80 (m, 2H), 1.77-1.70 (m, 2H) 397.sup.A
3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-
a]pyrazin-3-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-
yl)-5-fluoro-4-methylbenzenesulfonamide trifluoroacetate salt
##STR00561## 2-CH.sub.3, 3F 495.0 398.sup.A
5-(8-Amino-6-(trifluoromethyl)imidazo[1,2-
a]pyrazin-3-yl)-2-fluoro-N-(4-
(hydroxymethyl)bicyclo[2.1.1]hexan-1- yl)benzenesulfonamide
trifluoroacetate salt ##STR00562## 4-F 486.0 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.78 (s, 1H), 8.05-7.95 (m, 3H), 7.90 (s,
1H), 7.74- 7.56 (m, 3H), 3.34 (s, 2H), 1.74-1.63 (m, 2H), 1.49-1.41
(m, 2H), 1.40-1.29 (m, 2H), 1.12-1.03 (m, 2H) 399.sup.A
5-(8-Amino-6-(trifluoromethyl)imidazo[1,2-
a]pyrazin-3-yl)-2-chloro-N-(4-
(hydroxymethyl)bicyclo[2.1.1]hexan-1- yl)benzenesulfonamide
trifluoroacetate salt ##STR00563## 4-Cl 502.1 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.70 (s, 1H), 8.20 (d, J = 1.9 Hz, 1H), 8.03
(s, 1H), 7.98- 7.92 (m, 2H), 7.85 (d, J = 8.3 Hz, 1H), 7.70 (s,
2H), 3.33 (s, 2H), 1.73-1.63 (m, 2H), 1.48- 1.40 (m, 2H), 1.38-1.30
(m, 2H), 1.13-1.03 (m, 2H) 400.sup.A
5-(8-Amino-6-(trifluoromethyl)imidazo[1,2- a]pyrazin-3-yl)-N-(4-
(hydroxymethyl)bicyclo[2.1.1]hexan-1-yl)-2,4-
dimethylbenzenesulfonamide trifluoroacetate salt ##STR00564##
2-CH.sub.3, 4-CH.sub.3 496.1 .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 7.93 (s, 1H), 7.73 (s, 1H), 7.57 (s, 1H), 7.50 (s, 1H),
3.53 (s, 2H), 2.74 (s, 3H), 2.25 (s, 3H), 1.81-1.69 (m, 2H),
1.60-1.51 (m, 2H), 1.51-1.42 (m, 2H), 1.28-1.16 (m, 2H)
401.sup.B,Ex. 260 3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-
a]pyrazin-3-yl)-4-cyano-N-(4- (hydroxymethyl)bicyclo[2.1.1]hexan-1-
yl)benzenesulfonamide trifluoroacetate salt ##STR00565## 2-CN 493.1
.sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. 8.74 (s, 1H), 8.31 (d,
J = 8.2 Hz, 1H), 8.17 (d, J = 1.7 Hz, 1H), 8.08 (dd, J = 8.2, 1.8
Hz, 1H), 8.03 (s, 1H), 7.97 (s, 1H), 7.78 (s, 2H), 3.36 (s, 2H),
1.71-1.63 (m, 2H), 1.47-1.40 (m, 2H), 1.40-1.33 (m, 2H), 1.14-1.05
(m, 2H) 402.sup.A
5-(4-amino-2-methylimidazo[1,2-f][1,2,4]triazin-7-
yl)-2-fluoro-N-((1r,4r)-4-hydroxy-4-
methylcyclohexyl)-4-methylbenzenesulfonamide trifluoroacetate salt
##STR00566## 2-CH.sub.3 4-F 449.1 .sup.1H NMR (400 MHz, CD.sub.3CN)
.delta. 7.96 (d, J = 7.6 Hz, 1H), 7.62 (s, 1H), 7.34 (d, J = 11.2
Hz, 1H), 5.85 (d, J = 7.6 Hz, 1H), 3.33 (s, 1H), 2.41 (s, 1H), 2.35
(s, 3H), 2.17 (s, 3H), 1.82- 1.69 (m, 2H), 1.63-1.51 (m, 2H),
1.48-1.31 (m, 4H), 1.16 (s, 3H). 403.sup.A
5-(4-amino-2-methylimidazo[1,2-f][1,2,4]triazin-7-
yl)-2-chloro-N-(2-hydroxy-2-methylpropyl)-4-
methylbenzenesulfonamide trifluoroacetate salt ##STR00567##
2-CH.sub.3 4-Cl 425.1 404.sup.A
3-(4-amino-2-methylimidazo[1,2-f][1,2,4]triazin-7-
yl)-5-fluoro-N-(1-(hydroxymethyl)-2-
oxabicyclo[2.2.2]octan-4-yl)-4- methylbenzenesulfonamide
trifluoroacetate salt ##STR00568## 2-CH.sub.3 3-F 477.2 405.sup.A
5-(8-amino-6-(trifluoromethyl)imidazo[1,2-
a]pyrazin-3-yl)-N-((3S,6R)-6-
(cyanomethyl)tetrahydro-2H-pyran-3-yl)-2-fluoro-
4-methylbenzenesulfonamide trifluoroacetate salt ##STR00569## 4-Me
4-F 513.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.15 (d, J =
7.2 Hz, 1H), 7.82-7.74 (m, 2H), 7.70 (s, 1H), 7.65 (br s, 2H), 7.58
(d, J = 11.3 Hz, 1H), 3.82-3.64 (m, 1H), 3.57-3.37 (m,1H),
3.25-3.04 (m, 2H), 2.71 (dd, J = 17.0, 4.4 Hz, 1H), 2.59 (dd, J =
17.0, 6.7 Hz, 1H), 2.20 (s, 3H), 1.82-1.72 (m, 1H), 1.72-1.62 (m,
1H), 1.55-1.37 (m, 1H), 1.36-1.17 (m, 1H). 406.sup.B
3-(8-amino-6-(trifluoromethyl)imidazo[1,2-
a]pyrazin-3-yl)-N-((3S,6R)-6-
(cyanomethyl)tetrahydro-2H-pyran-3-yl)-4-
(methyl-d.sub.3)benzenesulfonamide ##STR00570## 2-CD.sub.3 498.2
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.87 (d, J = 7.8 Hz,
1H), 7.84-7.77 (m, 2H), 7.70-7.57 (m, 3H), 3.71 (d, J = 8.9 Hz,
1H), 3.50-3.38 (m, 1H), 3.17-2.94 (m, 2H), 2.70 (dd, J = 17.0, 4.0
Hz, 1H), 2.57 (dd, J = 17.0, 6.6 Hz, 1H), 1.76-1.67 (m, 1H),
1.67-1.58 (m, 1H), 1.46-1.31 (m, 1H), 1.31-1.14 (m, 1H). 407.sup.A
3-(8-amino-6-(trifluoromethyl)imidazo[1,2-
a]pyrazin-3-yl)-N-(2-hydroxy-2-methylpropyl)-4-
(trifluoromethyl)benzenesulfonamide ##STR00571## 2-CF.sub.3 498.1
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.27-8.10 (m, 2H), 8.05
(s, 1H), 7.90-7.59 (m, 5H), 4.39 (s, 1H), 2.73 (s, 2H), 1.03 (s,
6H). 408.sup.A (1-((5-(8-Amino-6-(trifluoromethyl)imidazo[1,2-
a]pyrazin-3-yl)-2-fluoro-4-
methylphenyl)sulfonyl)piperidin-3-yl)methanol ##STR00572## 2-Me 4-F
488.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.80 (s, 1H),
7.75 (s, 1H), 7.73 (d, J = 7.1 Hz, 1H), 7.65 (br s, 2H), 7.63 (d, J
= 11.4 Hz, 1H), 4.57 (t, J = 5.2 Hz, 1H), 3.71 (d, J = 9.1 Hz, 1H),
3.57 (d, J = 11.4 Hz, 1H), 3.36-3.26 (m, 1H), 3.22-3.10 (m, 1H),
2.61-2.42 (m, 1H), 2.32 (t, J = 10.7 Hz, 1H), 2.25 (s, 3H),
1.78-1.55 (m, 3H), 1.55-1.37 (m, 1H), 0.99 (q, J = 11.6 Hz, 1H).
.sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta. -66.62, -108.29.
409.sup.B (1-((3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-
a]pyrazin-3-yl)-4-(methyl-
d.sub.3)phenyl)sulfonyl)piperidin-3-yl)methanol ##STR00573##
2-CD.sub.3 473.1
TABLE-US-00018 TABLE 18 ##STR00574## LCMS Ex. Name --N(R).sub.2 R'
= [M + H].sup.+ No. NMR Spectra 410.sup.A
5-(4-Amino-2-(trifluoromethyl)imidazo[1,2-
f][1,2,4]triazin-7-yl)-2-chloro-N-((1r,4r)-4-hydroxy-4-
methylcyclohexyl)-4-methylbenzenesulfonamide trifluoroacetate salt
##STR00575## 2-CH.sub.3, 4-Cl 519.1 .sup.1H NMR (600 MHz,
DMSO-d.sub.6) .delta. 8.97 (s, 1H), 8.93 (s, 1H), 8.14 (s, 1H),
7.99 (s, 1H), 7.82 (d, J = 7.7 Hz, 1H), 7.75 (s, 1H), 3.18-3.08 (m,
1H), 2.37 (s, 3H), 1.64-1.54 (m, 2H), 1.54- 1.48 (m, 2H), 1.38-1.29
(m, 2H), 1.29-1.18 (m, 2H), 1.06 (s, 3H). .sup.19F NMR (376 MHz,
DMSO-d.sub.6) .delta. -69.12 (s), -74.96 (s). 411.sup.A
3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-
f][1,2,4]triazin-7-yl)-N-(4- (hydroxymethyl)bicyclo[2.1.1]hexan-1-
yl)benzenesulfonamide trifluoroacetate salt ##STR00576## -- 469.1
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.68-8.64 (m, 1H),
8.37-8.31 (m, 1H), 8.14 (s, 1H), 7.97- 7.90 (m, 1H), 7.72 (t, J =
7.9 Hz, 1H), 3.51 (s, 2H), 1.87-1.72 (m, 2H), 1.59-1.50 (m, 2H),
1.50-1.41 (m, 2H), 1.28-1.15 (m, 2H) 412.sup.A
5-(4-Amino-2-(trifluoromethyl)imidazo[1,2-
f][1,2,4]triazin-7-yl)-2-fluoro-N-((1r,4r)-4-hydroxy-4-
methylcyclohexyl)-4-methylbenzenesulfonamide trifluoroacetate salt
##STR00577## 2-CH.sub.3, 4-F 503.0 .sup.1H NMR (600 MHz,
DMSO-d.sub.6) .delta. 8.96 (s, 1H), 8.92 (s, 1H), 7.94 (s, 1H),
7.92 (d, J = 7.4 Hz, 1H), 7.91 (d, J = 7.5 Hz, 1H), 7.54 (d, J =
11.2 Hz, 1H), 3.23-3.09 (m, 1H), 2.34 (s, 3H), 1.67-1.56 (m, 2H),
1.56-1.42 (m, 2H), 1.40-1.21 (m, 4H), 1.06 (s, 3H). .sup.19F NMR
(376 MHz, DMSO-d.sub.6) .delta. -69.09 (s), -75.06 (s), -110.63
(s). 413.sup.A 5-(4-Amino-2-(trifluoromethyl)imidazo[1,2-
f][1,2,4]triazin-7-yl)-N-((1r,4r)-4-hydroxy-4-
methylcyclohexyl)-2,4-dimethylbenzenesulfonamide trifluoroacetate
salt ##STR00578## 2-CH.sub.3, 4-CH.sub.3 499.1 .sup.1H NMR (600
MHz, DMSO-d.sub.6) .delta. 8.94 (s, 1H), 8.90 (s, 1H), 7.98 (s,
1H), 7.92 (s, 1H), 7.63 (d, J = 7.7 Hz, 1H), 7.44 (s, 1H),
3.13-3.01 (m, 1H), 2.62 (s, 3H), 2.31 (s, 3H), 1.63-1.53 (m, 2H),
1.53-1.42 (m, 2H), 1.34-1.19 (m, 4H), 1.05 (s, 3H). .sup.19F NMR
(376 MHz, DMSO-d.sub.6) .delta. -69.06 (s), -74.96 (s). 414.sup.A
5-(4-Amino-2-(trifluoromethyl)imidazo[1,2-
f][1,2,4]triazin-7-yl)-2-chloro-N-(4-
cyanobicyclo[2.1.1]hexan-1-yl)benzenesulfonamide ##STR00579## 4-Cl
498.0 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.99 (s, 1H), 8.25
(d, J = 8.1 Hz, 1H), 8.16 (s, 1H), 7.77 (d, J = 8.4 Hz, 1H),
2.17-2.05 (m, 2H), 1.99-1.88 (m, 2H), 1.88-1.77 (m, 2H), 1.74-1.63
(m, 2H) 415.sup.A 3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-
f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-
yl)benzenesulfonamide trifluoroacetate salt ##STR00580## -- 464.1
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.98 (s, 1H), 8.96 (s,
1H), 8.79 (s, 1H), 8.66-8.60 (m, 1H), 8.33-8.26 (m, 2H), 7.91-7.83
(m, 1H), 7.78 (t, J = 7.9 Hz, 1H) 2.03-1.94 (m, 2H), 1.91-1.82 (m,
2H), 1.75-1.67 (m, 2H), 1.66-1.55 (m, 2H) 416.sup.A
3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-
f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-
yl)-5-fluoro-4-methylbenzenesulfonamide trifluoroacetate salt
##STR00581## 2-CH.sub.3, 3-F 496.1 417.sup.A
5-(4-Amino-2-(trifluoromethyl)imidazo[1,2-
f][1,2,4]triazin-7-yl)-N-(4-cyanobicyclo[2.1.1]hexan-1-
yl)-2-fluorobenzenesulfonamide trifluoroacetate salt ##STR00582##
4-F 482.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.10 (s, 1H),
8.97 (s, 1H), 8.95 (s, 1H), 8.66 (dd, J = 7.0, 2.2 Hz, 1H), 8.33
(ddd, J = 8.5, 4.5, 2.4 Hz, 1H), 8.28 (s, 1H), 7.71-7.61 (m, 1H),
2.07- 1.97 (m, 2H), 1.90-1.82 (m, 2H), 1.76-1.68 (m, 2H), 1.68-1.59
(m, 2H) 418.sup.A 5-(4-Amino-2-(trifluoromethyl)imidazo[1,2-
f][1,2,4]triazin-7-yl)-2-fluoro-N-(4-
(hydroxymethyl)bicyclo[2.1.1]hexan-1- yl)benzenesulfonamide
##STR00583## 4-F 487.2 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
8.89 (br s, 3H), 8.61 (dd, J = 6.8, 1.6 Hz, 1H), 8.37-8.27 (m, 1H),
8.25 (s, 1H), 7.63 (t, J = 9.3 Hz, 1H), 4.35 (t, J = 4.9 Hz, 1H),
1.74-1.61 (m, 2H), 1.46-1.37 (m, 2H), 1.37-1.26 (m, 2H), 1.12-0.94
(m, 2H) 419.sup.A 5-(4-Amino-2-(trifluoromethyl)imidazo[1,2-
f][1,2,4]triazin-7-yl)-2-chloro-N-(4-
(hydroxymethyl)bicyclo[1.1.1]hexan-1- yl)benzenesulfonamide
##STR00584## 4-Cl 503.1 420.sup.B
3-(4-Amino-2-(trifluoromethyl)imidazo[2,1-
f][1,2,4]triazin-7-yl)-N-(3-
(hydroxymethyl)bicyclo[2.1.1]pentan-1-yl)-4-(methyl-
d.sub.3)benzenesulfonamide trifluoroacetate salt ##STR00585##
2-CD.sub.3 472.1 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.96 (d,
J = 1.9 Hz, 1H), 7.90 (dd, J = 8.1, 2.0 Hz, 1H), 7.82 (s, 1H), 7.61
(d, J = 8.1 Hz, 1H), 3.53 (s, 2H), 1.75 (s, 6H)
TABLE-US-00019 TABLE 19 ##STR00586## LCMS Ex. Name R.sup.8 R' = [M
+ H].sup.+ No. .sup.1H NMR 421.sup.Ex17
5-(8-amino-6-(2-fluorophenyl)imidazo[1,2-a]pyrazin-3-yl)-
2-fluoro-N-((1r,4r)-4-hydroxy-4-
methylcyclohexyl)benzenesulfonamide ##STR00587## 4-F 514.3 .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 8.12-8.05 (m, 2H), 8.05-7.93
(m, 3H), 7.84 (s, 1H), 7.72-7.59 (m, 1H), 7.44-7.36 (m, 1H),
7.34-7.17 (m, 4H), 4.15 (s, 1H), 3.26-3.15 (m, 1H), 1.67-1.55 (m,
2H), 1.55-1.42 (m, 2H), 1.39-1.16 (m, 4H), 1.05 (s, 3H).
422.sup.Ex17
5-(8-amino-6-(3-fluoropyridin-4-yl)imidazo[1,2-a]pyrazin-
3-yl)-2-fluoro-N-((1r,4r)-4-hydroxy-4-
methylcyclohexyl)benzenesulfonamide ##STR00588## 4-F 515.2 .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 8.62 (d, J = 3.2 Hz, 1H), 8.53
(d, J = 5.0 Hz, 1H), 8.25 (s, 1H), 8.15-8.07 (m, 1H), 8.06-7.92 (m,
3H), 7.87 (s, 1H), 7.65 (dd, J = 9.1, 9.1 Hz, 1H), 7.39 (s, 2H),
4.15 (s, 1H), 3.24-3.12 (m, 1H), 1.66-1.55 (m, 2H), 1.54-1.43 (m,
2H), 1.37- 1.18 (m, 4H), 1.05 (s, 3H). 423.sup.Ex17
5-(8-amino-6-(2-fluoro-4-
(hydroxymethyl)phenyl)imidazo[1,2-a]pyrazin-3-yl)-2-
fluoro-N-((1r,4r)-4-hydroxy-4- methylcyclohexyl)benzenesulfonamide
##STR00589## 4-F 544.4 .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta.
8.10-8.03 (m, 2H), 8.03-7.94 (m, 3H), 7.83 (s, 1H), 7.69-7.60 (m,
1H), 7.28-7.16 (m, 4H), 5.34 (br s, 1H), 4.53 (s, 2H), 4.14 (s,
1H), 3.24- 3.17 (m, 1H), 1.67-1.56 (m, 2H), 1.55-1.43 (m, 2H),
1.36-1.20 (m, 4H), 1.04 (s, 3H).
Example 424.
3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methyl-N-(1-methyl-2-oxabi-
cyclo[2.1.1]hexan-4-yl)benzenesulfonamide Trifluoroacetate Salt
##STR00590##
[1144] Step 1. (3-Methylenecyclobutane-1,1-diyl)dimethanol
##STR00591##
[1146] To a suspension of methyltriphenylphosphonium bromide (970
mg, 2.72 mmol) in THF (8 mL) at 0.degree. C. was added potassium
tert-butoxide (1.0 M/THF) (2.72 mL, 2.72 mmol). The ice bath was
removed and the reaction mixture was stirred at room temperature
for 1 h. The resulting yellow solution was cooled to 0.degree. C.
and a solution of diisopropyl 3-oxocyclobutane-1,1-dicarboxylate
(506 mg, 2.09 mmol, Synthonix) in THF (4 mL) was added dropwise via
cannula. The ice bath was removed and the reaction mixture was
stirred at room temperature for 1.5 h. The reaction was quenched
with saturated NH.sub.4Cl and extracted with EtOAc. The organic
extracts were washed with brine, dried over MgSO.sub.4, filtered,
and concentrated. The residue was purified by flash chromatography
(0-50% EtOAc/hexanes). The product was not dried under high vacuum
due to volatility concerns.
[1147] To a solution of diisopropyl
3-methylenecyclobutane-1,1-dicarboxylate (502 mg, 2.09 mmol) in THF
(6 mL) at 0.degree. C. was added a solution of lithium aluminum
hydride (2.0 M/THF, 3.13 mL, 6.27 mmol) dropwise. The reaction
mixture was warmed to room temperature and stirred for 0.5 h. The
reaction mixture was diluted with ether and cooled to 0.degree. C.
The reaction was quenched by the careful addition of 0.24 mL
H.sub.2O, followed by 0.24 mL 15% NaOH, and finally 0.72 mL
H.sub.2O. The resulting mixture was warmed to room temperature and
stirred for 15 min. Magnesium sulfate was added and the solids were
filtered off. The filter cake was washed with ether and the
filtrate was concentrated to afford the product as a colorless oil
(180 mg, 67%) that was used without purification.
Step 2. (1-(Iodomethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)methanol
(12248-19)
##STR00592##
[1149] To a solution of (3-methylenecyclobutane-1,1-diyl)dimethanol
(1.66 g, 12.95 mmol) in MeCN (50 mL) was added sodium bicarbonate
(1.63 g, 19.4 mmol) and N-iodosuccinimide (3.50 g, 15.5 mmol)
sequentially. The reaction mixture was stirred at room temperature
for 1 h. The reaction was quenched with sat. NaS.sub.2O.sub.3,
partitioned between water and EtOAc, and the layers were separated.
The organic layer was washed with brine, dried over MgSO.sub.4,
filtered and concentrated. The residue was purified by flash
chromatography (0-100% EtOAc/hexanes) to afford the product as a
yellow semi-solid (1.97 g, 60%) contaminated with succinimide.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.91 (s, 2H), 3.77 (s,
2H), 3.48 (s, 2H), 1.79-1.70 (m, 2H), 1.70-1.61 (m, 2H). LCMS
calculated for C.sub.7H.sub.12IO.sub.2 (M+H).sup.+: m/z=255.0;
found: 255.0.
Step 3. 1-Methyl-2-oxabicyclo[2.1.1]hexane-4-carboxylic Acid
##STR00593##
[1151] To a solution of
(1-(iodomethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)methanol (500 mg,
1.97 mmol) in methanol (6.0 mL) was added Pd--C (10 wt %, 105 mg,
0.098 mmol), followed by triethylamine (0.41 mL, 2.95 mmol). The
atmosphere was replaced with hydrogen and the reaction mixture was
vigorously stirred under 1 atm of hydrogen for 5 h. The reaction
mixture was filtered through a pad of Celite.RTM., concentrated,
and the residue was used without further purification.
[1152] A solution of
(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)methanol (250 mg, 1.95
mmol) in CH.sub.2C.sub.2 (3 mL)/acetonitrile (3.00 mL)/water (3.00
mL) was cooled to 0.degree. C. and stirred rapidly while sodium
periodate (1.25 g, 5.9 mmol) and ruthenium(III) chloride hydrate
(44.0 mg, 0.20 mmol) were added. The ice bath was removed and the
solution was stirred at room temperature for 4 h. The reaction
mixture was diluted with EtOAc and stirred while 1 N HCl was added
until all solids dissolved. The layers were separated and the
aqueous layer was extracted with EtOAc. The combined extracts were
washed with 10% NaHSO.sub.3 solution, brine, dried over MgSO.sub.4,
filtered, and concentrated. The residue was purified by flash
chromatography (0-20% MeOH/DCM) to afford the title compound (142
mg, 51%).
Step 4. Benzyl 1-methyl-2-oxabicyclo[2.1.1]hexan-4-ylcarbamate
##STR00594##
[1154] To a solution of
1-methyl-2-oxabicyclo[2.1.1]hexane-4-carboxylic acid (142 mg, 1.0
mmol) in toluene (3.0 mL) was added triethylamine (0.28 mL, 2.00
mmol), followed by diphenylphosphoryl azide (0.32 mL, 1.50 mmol).
The reaction mixture was stirred at room temperature for 1 h, then
heated to reflux for 2 h. The reaction mixture was then cooled to
room temperature and benzyl alcohol (0.208 mL, 2.0 mmol) was added.
The resulting solution was heated to reflux overnight. After
cooling to room temperature, the reaction mixture was concentrated
in vacuo and purified by flash chromatography (0-50% EtOAc/hexanes)
to afford the product as a light yellow solid (contaminated with
some benzyl alcohol). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.42-7.35 (m, 5H, overlapped with benzyl alcohol), 5.12 (s, 2H),
3.80 (s, 2H), 2.03-1.87 (m, 3H), 1.75 (m, 1H), 1.46 (s, 3H). LCMS
calculated for C.sub.14H.sub.18NO.sub.3 (M+H).sup.+: m/z=248.1;
found: 248.1.
Step 5. 1-Methyl-2-oxabicyclo[2.1.1]hexan-4-amine Hydrochloride
##STR00595##
[1156] To a solution of benzyl
(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)carbamate (145 mg, 0.59
mmol) in MeOH (4.0 mL) was added Pd--C (10 wt %, 31.2 mg, 29
.mu.mol). The atmosphere was replaced with hydrogen and the
reaction mixture was vigorously stirred under 1 atm of hydrogen for
1 h. The reaction mixture was filtered through a pad of
Celite.RTM., treated with 4 M HCl/dioxane (to form the
hydrochloride salt), concentrated, and the residue was used without
purification. LCMS calculated for C.sub.6H.sub.12NO (M+H).sup.+:
m/z=114.1; found: 114.1.
Step 6. 7-o-tolylimidazo[1,2-f][1,2,4]triazin-4-amine
##STR00596##
[1158] A mixture of 7-bromoimidazo[2,1-j][1,2,4]triazin-4-amine
(300 mg, 1.40 mmol), o-tolylboronic acid (210 mg, 1.54 mmol), and
Dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II)
dichloromethane adduct (57 mg, 0.07 mmol) was taken up in dioxane
(8 mL)/water (2 mL) and potassium carbonate (484 mg, 3.50 mmol) was
added. The reaction mixture was sparged with N.sub.2 and heated to
100.degree. C. for 3 h. Upon cooling to room temperature, the
product precipitated. The suspension was cooled in an ice bath and
diluted with ether. The solid was filtered, washed with ether, and
air dried to yield the title compound as a grey solid (316 mg,
100%). LCMS calculated for C.sub.12H.sub.12N.sub.5(M+H).sup.+:
m/z=226.1; found: 226.1.
Step 7.
3-(4-aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methylbenzene-1-sul-
fonyl chloride
##STR00597##
[1160] To a suspension of
7-(o-tolyl)imidazo[2,1-f][1,2,4]triazin-4-amine (800 mg, 3.55 mmol)
in DCM (10 ml) at 0.degree. C. was added chlorosulfonic acid (8 ml,
119 mmol) dropwise until complete dissolution of the starting
material (SM) was observed. The ice bath was removed and the
resulting black solution was allowed to warm to room temperature.
After stirring for 1 h, thionyl chloride (0.78 ml, 10.7 mmol) was
added. The reaction mixture was heated to 50.degree. C. and stirred
for 0.5 h. The reaction mixture was cooled to room temperature,
diluted with DCM, and carefully added to a rapidly stirring mixture
of DCM and ice chips. The precipitated solid was filtered and the
filtrate was transferred to a separatory funnel. The layers were
separated and the aqueous layer was extracted with DCM. The
combined organic layers were dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated. The resulting solid was combined with
the precipitate to yield the title compound (977 mg, 85%). 1H NMR
(400 MHz, DMSO) .delta. 9.79 (s, 1H), 9.46 (s, 1H), 8.37 (s, 1H),
8.07 (s, 1H), 7.67 (s, 1H), 7.65 (d, J=7.9 Hz, 1H), 7.37 (d, J=7.9
Hz, 1H), 2.22 (s, 3H). LCMS calculated for
C.sub.12H.sub.11ClN.sub.5O.sub.2S (M+H).sup.+: m/z=324.1; found:
324.0.
Step 8.
3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methyl-N-(1-methyl--
2-oxabicyclo[2.1.1]hexan-4-yl)benzenesulfonamide Trifluoroacetate
Salt
[1161] To a solution of 1-methyl-2-oxabicyclo[2.1.1]hexan-4-amine
hydrochloride (6.93 mg, 0.05 mmol) and DIPEA (16 .mu.L, 0.09 mmol)
in DMA (2.0 mL) at 0.degree. C. was added a solution of
3-(4-aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methylbenzene-1-sulfonyl
chloride (10.0 mg, 0.03 mmol) in DMA (1 mL) dropwise. The 0.degree.
C. bath was removed, and the reaction mixture was stirred at room
temp for 1 h. The solution was diluted with MeOH and purified by
prep HPLC (pH 2). .sup.1H NMR (500 MHz, DMSO) .delta. 8.71 (s, 1H),
8.46 (s, 1H), 8.35 (s, 1H), 8.09 (s, 1H), 7.96 (d, J=2.0 Hz, 1H),
7.83 (s, 1H), 7.82 (dd, J=8 Hz, 2 Hz, 1H), 7.62 (d, J=8.2 Hz, 1H),
3.52 (s, 2H), 2.35 (s, 3H), 1.62 (dd, J=4.4, 1.5 Hz, 2H), 1.45 (dd,
J=4.4, 1.6 Hz, 2H), 1.25 (s, 3H). LCMS calculated for
C.sub.18H.sub.21N.sub.6O.sub.3S (M+H).sup.+: m/z=401.1; found:
401.1.
Example 425.
3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methyl-N-(1-m-
ethyl-2-oxabicyclo[2.1.1]hexan-4-yl)benzenesulfonamide
Trifluoroacetate Salt
##STR00598##
[1163] This compound was prepared according to the procedure
described for Example 424, Step 8 utilizing
3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylbenzene-
-1-sulfonyl chloride (Example 472, Step 8) instead of
3-(4-aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methylbenzene-1-sulfonyl
chloride (Example 424, Step 7). .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 8.75 (s, 1H), 7.90 (dd, J=8.1, 2.0 Hz, 1H), 7.84 (d, J=2.0
Hz, 1H), 7.83 (s, 1H), 7.68 (d, J=8.2 Hz, 1H), 7.56 (s, 1H), 3.52
(s, 2H), 2.27 (s, 3H), 1.61 (dd, J=4.4, 1.5 Hz, 2H), 1.45 (dd,
J=4.3, 1.6 Hz, 2H), 1.24 (s, 3H). LCMS calculated for
C.sub.20H.sub.21F.sub.3N.sub.5O.sub.3S (M+H): m/z=468.1; found:
468.1.
Example 426.
3-(4-Amino-2-methylimidazo[1,2-f][1,2,4]triazin-7-yl)-4-trideuteromethyl--
N-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)benzenesulfonamide
Trifluoroacetate Salt
##STR00599##
[1165] This compound was prepared according to the procedure
described for Example 424, Step 8 utilizing
3-(4-amino-2-methylimidazo[1,2-f][1,2,4]triazin-7-yl)-4-trideuteromethylb-
enzene-1-sulfonyl chloride (Example 253, Step 3) instead of
3-(4-aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methylbenzene-1-sulfonyl
chloride (Example 424, Step 7). LCMS calculated for
C.sub.19H.sub.20D.sub.3N.sub.6O.sub.3S (M+H)f: m/z=418.2; found:
418.2.
Example 427.
3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-7-yl)-N-(1-(hy-
droxymethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)-4-methylbenzenesulfonamide
Trifluoroacetate Salt
##STR00600##
[1166] Step 1.
(4-(Hydroxymethyl)-2-oxabicyclo[2.1.1]hexan-1-yl)methyl Acetate
##STR00601##
[1168] To a solution of
(1-(iodomethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)methanol (874 mg, 3.4
mmol, Example 424, Step 2) in DMF (6.0 mL) was added cesium acetate
(990 mg, 5.2 mmol), and the reaction mixture was heated to
100.degree. C. for 2 h. The reaction mixture was partitioned
between water and EtOAc and the layers were separated. The organic
layer was washed with brine, dried over MgSO.sub.4, filtered and
concentrated. The residue was purified by flash chromatography
(0-100% EtOAc/hexanes, followed by 15% MeOH/DCM) to afford the
title compound (326 mg, 51%). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 4.34 (s, 2H), 3.90 (s, 2H), 3.75 (s, 2H), 2.10 (s, 3H),
1.74 (dd, J=4.6, 1.3 Hz, 2H), 1.64 (dd, J=4.6, 1.5 Hz, 2H). LCMS
calculated for C.sub.9H.sub.15O.sub.4(M+H).sup.+: m/z=187.1; found:
187.0.
Step 2. 1-(Acetoxymethyl)-2-oxabicyclo[2.1.1]hexane-4-carboxylic
Acid
##STR00602##
[1170] A solution of
(4-(hydroxymethyl)-2-oxabicyclo[2.1.1]hexan-1-yl)methyl acetate
(329 mg, 1.8 mmol) in CH.sub.2Cl.sub.2 (3 mL)/acetonitrile (3.00
mL)/water (3.00 mL) at 0.degree. C. was stirred rapidly while
sodium periodate (1.13 g, 5.30 mmol) and ruthenium(III) chloride
hydrate (40 mg, 0.18 mmol) were added. The ice bath was removed,
and the solution was stirred at room temperature for 4 h. The
reaction was diluted with EtOAc and stirred while 1M HCl was added
until all solids dissolved. The layers were separated and the
aqueous layer was extracted with EtOAc. The combined extracts were
washed with 10% NaHSO.sub.3 solution, brine, dried over MgSO.sub.4,
filtered, and concentrated. The residue was purified by flash
chromatography (0-20% MeOH/DCM) to afford the title compound as a
white solid (340 mg, 96%). LCMS calculated for
C.sub.9H.sub.13O.sub.5(M+H).sup.+: m/z=201.1; found: 201.1.
Step 3.
(4-(Benzyloxycarbonylamino)-2-oxabicyclo[2.1.1]hexan-1-yl)methyl
Acetate
##STR00603##
[1172] To a solution of
1-(acetoxymethyl)-2-oxabicyclo[2.1.1]hexane-4-carboxylic acid (350
mg, 1.75 mmol) in toluene (5.0 mL) was added triethylamine (0.49
mL, 3.50 mmol), followed by diphenylphosphoryl azide (0.56 mL, 2.62
mmol). The reaction mixture was stirred at room temperature for 1
h, then heated to reflux for 2 h. The reaction mixture was then
cooled to room temperature and benzyl alcohol (0.36 mL, 3.50 mmol)
was added. The resulting solution was heated to reflux overnight.
After cooling to room temperature, the reaction mixture was
concentrated in vacuo and purified by flash chromatography (0-50%
EtOAc/hexanes) to afford the desired product as a colorless oil
(391 mg, 73%). LCMS calculated for C.sub.1-6H.sub.20NO.sub.5
(M+H).sup.+: m/z=306.1; found: 306.1.
Step 4. Benzyl
1-(hydroxymethyl)-2-oxabicyclo[2.1.1]hexan-4-ylcarbamate
##STR00604##
[1174] To a solution of
(4-(((benzyloxy)carbonyl)amino)-2-oxabicyclo[2.1.1]hexan-1-yl)methyl
acetate (391 mg, 1.28 mmol) in MeOH (6.0 mL) was added potassium
carbonate (230 mg, 1.67 mmol) at 0.degree. C. The reaction mixture
was warmed to room temperature and stirred for 30 min. The reaction
mixture was partitioned between water and EtOAc, and the layers
were separated. The aqueous layer was extracted with EtOAc and the
combined organic layers were washed with brine, dried over
MgSO.sub.4, filtered, and concentrated. The resulting white solid
was used without purification (316 mg, 94%). LCMS calculated for
C.sub.14H.sub.18NO.sub.4 (M+H).sup.+: m/z=264.1; found: 264.2.
Step 5. (4-Amino-2-oxabicyclo[2.1.1]hexan-1-yl)methanol
##STR00605##
[1176] To a solution of benzyl
(1-(hydroxymethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)carbamate (40 mg,
0.152 mmol) in MeOH (3 mL) was added palladium hydroxide on carbon
(20 wt %, 10.7 mg, 0.02 mmol). The atmosphere was replaced with
hydrogen and the reaction mixture was vigorously stirred under 1
atm of hydrogen for 1 h. The reaction mixture was filtered through
a pad of Celite.RTM., concentrated in vacuo, and the residue was
used without purification. LCMS calculated for
C.sub.6H.sub.12NO.sub.2 (M+H).sup.+: m/z=130.1; found: 130.1.
Step 6.
3-(4-Amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-7-yl)-N-
-(1-(hydroxymethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)-4-methylbenzenesulfonam-
ide Trifluoroacetate Salt
[1177] To a solution of
(4-amino-2-oxabicyclo[2.1.1]hexan-1-yl)methanol (4.95 mg, 0.038
mmol) and DIPEA (0.013 mL, 0.077 mmol) in DMA (2.0 mL) at 0.degree.
C. was added a solution of
3-(4-amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-7-yl)-4-methyl-
benzene-1-sulfonyl chloride (10 mg, 0.026 mmol, 4N CF.sub.3) in DMA
(1 mL) dropwise. The 0.degree. C. bath was removed, and the
reaction mixture was stirred at room temp for 1 h. The solution was
diluted with MeOH and purified by prep HPLC (pH 2). LCMS calculated
for C.sub.19H.sub.20F.sub.3N.sub.6O.sub.4S (M+H).sup.+: m/z=485.1;
found: 485.0.
Example 428.
3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-N-(1-(hydroxyme-
thyl)-2-oxabicyclo[2.1.1]hexan-4-yl)-4-methylbenzenesulfonamide
Trifluoroacetate Salt
##STR00606##
[1179] This compound was prepared according to the procedure
described for Example 427, Step 6 utilizing
3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylbenzene-
-1-sulfonyl chloride (Example 472, Step 8) instead of
3-(4-amino-2-(trifluoromethyl)imidazo[1,2-f][1,2,4]triazin-7-yl)-4-methyl-
benzene-1-sulfonyl chloride (4N CF3). LCMS calculated for
C.sub.20H.sub.21F.sub.3N.sub.5O.sub.4S (M+H).sup.+: m/z=484.1;
found: 484.1.
Example 429.
3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-N-(1-cyano-2-ox-
abicyclo[2.1.1]hexan-4-yl)-4-methylbenzenesulfonamide
Trifluoroacetate Salt
##STR00607##
[1180] Step 1. tert-butyl
1-(hydroxymethyl)-2-oxabicyclo[2.1.1]hexan-4-ylcarbamate
##STR00608##
[1182] To a solution of
(4-amino-2-oxabicyclo[2.1.1]hexan-1-yl)methanol (30 mg, 0.23 mmol,
Example 427, Step 5) in THF (3 mL) was added sodium bicarbonate
(sat. aq.) (2 mL) followed by di-tert-butyl dicarbonate (76 mg,
0.35 mmol). The reaction mixture was vigorously stirred at room
temperature for 4 h. The reaction mixture was partitioned between
water and EtOAc, and the layers were separated. The aqueous layer
was extracted with EtOAc and the combined organic layers were
washed with brine, dried over MgSO.sub.4, filtered, and
concentrated. The residue was purified by flash chromatography
(0-100% EtOAc/hexanes) to afford the product as a white solid (31.5
mg, 59%). LCMS calculated for C.sub.11H.sub.19NO.sub.4Na
(M+Na).sup.+: m/z=252.1; found: 252.1.
Step 2. tert-butyl
1-formyl-2-oxabicyclo[2.1.1]hexan-4-ylcarbamate
##STR00609##
[1184] To a solution of tert-butyl
(1-(hydroxymethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)carbamate (31.5
mg, 0.14 mmol) in DCM (3.0 mL) was added sodium bicarbonate (23 mg,
0.28 mmol) and Dess-Martin periodinane (87 mg, 0.21 mmol). The
reaction mixture was stirred at room temperature for 1 h, at which
point TLC indicated complete consumption of SM. The reaction was
diluted with DCM, quenched with saturated Na.sub.2S.sub.2O.sub.3
and saturated NaHCO.sub.3 (1 mL each), and vigorously stirred until
two clear layers were obtained (10 min). The layers were separated
and the organic layer was dried over MgSO.sub.4, filtered, and
concentrated. The residue was used without purification.
Step 3. (E)-tert-butyl
1-((hydroxyimino)methyl)-2-oxabicyclo[2.1.1]hexan-4-ylcarbamate
##STR00610##
[1186] To a solution of tert-butyl
(1-formyl-2-oxabicyclo[2.1.1]hexan-4-yl)carbamate (31.5 mg, 0.14
mmol) in pyridine (3.0 mL) was added hydroxylamine hydrochloride
(29 mg, 0.42 mmol) and the reaction mixture was stirred at room
temperature for 1 h. The reaction mixture was partitioned between
water and EtOAc, and the layers were separated. The organic layer
was washed with brine, dried over MgSO.sub.4, filtered, and
concentrated. The residue was dried under high vac and used without
purification. LCMS calculated for C.sub.11H.sub.18N.sub.2O.sub.4Na
(M+Na).sup.+: m/z=265.1; found: 265.1.
Step 4. 4-Amino-2-oxabicyclo[2.1.1]hexane-1-carbonitrile
Hydrochloride Salt
##STR00611##
[1188] To a solution of tert-butyl
(E)-(1-((hydroxyimino)methyl)-2-oxabicyclo[2.1.1]hexan-4-yl)carbamate
(33 mg, 0.14 mmol) and triethylamine (76 .mu.L, 0.55 mmol) in DCM
(3.0 mL) (gently heated to dissolve, then cooled to 0.degree. C.)
was added methanesulfonyl chloride (32 .mu.L, 0.41 mmol). The ice
bath was removed and the reaction mixture was allowed to stir at
room temperature for 1 h. The reaction was quenched with saturated
NaHCO.sub.3 and diluted with DCM. The layers were separated and the
organic layer was dried over MgSO.sub.4, filtered, and
concentrated. The residue was stirred in HCl (4 M/dioxane) (2 mL,
65.8 mmol) for 30 min and concentrated to afford the product, which
was used without purification. LCMS calculated for
C.sub.6H.sub.9N.sub.2O (M+H).sup.+: m/z=125.1; found: 125.1.
Step 5.
3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-N-(1-cya-
no-2-oxabicyclo[2.1.1]hexan-4-yl)-4-methylbenzenesulfonamide
Trifluoroacetate Salt
[1189] Prepared according to the procedure described for Example
428 utilizing 4-amino-2-oxabicyclo[2.1.1]hexane-1-carbonitrile
hydrochloride salt instead of
(4-amino-2-oxabicyclo[2.1.1]hexan-1-yl)methanol. LCMS calculated
for C.sub.20H.sub.18F.sub.3N.sub.6O.sub.3S (M+H).sup.+: m/z=479.1;
found: 479.1.
Example 430.
3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-((1s,4s)-4-(cyanomethyl)bi-
cyclo[2.2.1]heptan-1-yl)-4-methylbenzenesulfonamide
Trifluoroacetate Salt
##STR00612##
[1190] Step 1.
4-(methoxycarbonyl)bicyclo[2.2.I]heptane-1-carboxylic Acid
##STR00613##
[1192] To a solution of dimethyl bicyclo
[2.2.1]heptane-1,4-dicarboxylate (1 g, 4.71 mmol, Ark Pharm,
AK313189) in THF (32 mL) at 15.degree. C. (ice water bath) was
added a solution of sodium hydroxide (188 mg, 4.71 mmol) in
methanol (2 mL). After the addition was complete, white solids
began to precipitate. The reaction mixture was stirred at room temp
overnight. The reaction mixture was concentrated to dryness,
slurried in hexanes, filtered, and washed with hexanes. The
resulting sodium carboxylate salt was dissolved in water, and
slowly treated with 1 N aqueous hydrochloric acid until pH 4. The
suspension was diluted with ethyl acetate and transferred to a
separatory funnel. The layers were separated and the aqueous layer
was further extracted with ethyl acetate. The combined organic
layers were washed with brine, dried over MgSO.sub.4, and
concentrated. The resulting white solid was used without
purification. .sup.1H NMR (400 MHz, DMSO) .delta. 3.62 (s, 3H),
1.93 (app d, J=6.6 Hz, 4H), 1.77 (s, 2H), 1.60 (q, J=9.2, 8.7 Hz,
4H).
Step 2. Methyl
4-(benzyloxycarbonylamino)bicyclo[2.2.I]heptane-1-carboxylate
##STR00614##
[1194] To a solution of
4-(methoxycarbonyl)bicyclo[2.2.1]heptane-1-carboxylic acid (500 mg,
2.52 mmol) in toluene (5.0 mL) was added DIPEA (0.88 mL, 5.04
mmol), followed by diphenylphosphoryl azide (0.65 mL, 3.03 mmol),
and the reaction mixture was heated to 60.degree. C. for 0.5 h,
then to reflux for 2 h. The reaction mixture was then cooled to
50.degree. C. and benzyl alcohol (0.53 mL, 5.04 mmol) was added.
The resulting solution was heated to reflux for 24 h. After cooling
to room temperature, the reaction mixture was diluted with EtOAc,
washed with water and brine, dried over MgSO.sub.4, filtered and
concentrated. The residue was purified by flash chromatography
(0-50% EtOAc/hexanes) to afford the product as a colorless oil,
which was contaminated with a large amount of benzyl alcohol. LCMS
calculated for C.sub.17H.sub.22NO.sub.4 (M+H).sup.+: m/z=304.2;
found: 304.1.
Step 3. Benzyl
4-(hydroxymethyl)bicyclo[2.2.I]heptan-1-ylcarbamate
##STR00615##
[1196] To a solution of methyl
4-(((benzyloxy)carbonyl)amino)bicyclo[2.2.1]heptane-1-carboxylate
(500 mg, 1.65 mmol) in THF (5.0 mL) was added lithium borohydride
(180 mg, 8.24 mmol) at room temperature and the reaction mixture
was stirred overnight. The reaction mixture was cooled to 0.degree.
C., and slowly quenched by the dropwise addition of saturated
NH.sub.4Cl. After warming to room temperature, the reaction mixture
was partitioned between water and EtOAc, and the layers were
separated. The organic layer was washed with brine, dried over
MgSO.sub.4, filtered, and concentrated. The residue was purified by
flash chromatography (0-50-70% EtOAc/hexanes) to afford the product
as a colorless oil (398 mg, 88%). LCMS calculated for
C.sub.1-6H.sub.22NO.sub.3 (M+H).sup.+: m/z=276.2; found: 276.1.
Step 4. (4-(Benzyloxycarbonylamino)bicyclo[2.2.I]heptan-1-yl)methyl
Methanesulfonate
##STR00616##
[1198] To a solution of benzyl
4-(hydroxymethyl)bicyclo[2.2.1]heptan-1-yl)carbamate (200 mg, 0.73
mmol) and triethylamine (0.51 mL, 3.63 mmol) in DCM (3.0 mL) at
0.degree. C. was added methanesulfonyl chloride (0.11 mL, 1.45
mmol) dropwise. After stirring at this temperature for min, the
reaction mixture was allowed to warm to room temperature and stir
for 2 h. The reaction was quenched with saturated NaHCO.sub.3 and
diluted with DCM. The layers were separated and the organic layer
was dried over MgSO.sub.4, filtered and concentrated. The residue
was purified by flash chromatography (0-50% EtOAc/hexanes) to
afford the product as a colorless oil (252 mg, 98%). LCMS
calculated for C.sub.17H.sub.23NO.sub.5SNa (M+Na).sup.+: m/z=376.1;
found: 376.1.
Step 5. Benzyl
4-(cyanomethyl)bicyclo[2.2.I]heptan-1-ylcarbamate
##STR00617##
[1200] To a solution of
4-(((benzyloxy)carbonyl)amino)bicyclo[2.2.1]heptan-1-yl)methyl
methanesulfonate (250 mg, 0.71 mmol) in DMSO (4.0 mL) was added
potassium cyanide (461 mg, 7.07 mmol) and the reaction mixture was
heated to 100.degree. C. overnight. The reaction mixture was
diluted with EtOAc and washed with water and brine. The organic
layer was dried over MgSO.sub.4, filtered, and concentrated. The
residue was purified by flash chromatography (0-50% EtOAc/hexanes)
to afford the product as a colorless oil (165 mg, 82%). LCMS
calculated for C.sub.17H.sub.21N.sub.2O.sub.2 (M+H).sup.+:
m/z=285.2; found: 285.1.
Step 6. 2-(4-Aminobicyclo[2.2.I]heptan-1-yl)acetonitrile
##STR00618##
[1202] To a solution of benzyl
4-(cyanomethyl)bicyclo[2.2.1]heptan-1-yl)carbamate (165 mg, 0.58
mmol) in MeOH (4 mL) was added palladium on carbon (10 wt %, 30.9
mg, 29 .mu.mol). The vial was purged with hydrogen and the reaction
mixture was stirred under 1 atm of hydrogen for 2 h. The reaction
mixture was filtered through a pad of Celite*, which was rinsed
with additional MeOH. The volatiles were removed in vacuo to afford
the product as a colorless oil that was used without purification.
LCMS calculated for C.sub.9H.sub.15N.sub.2(M+H).sup.+: m/z=151.1;
found: 151.1.
Step 7.
3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-((s,4s)-4-(cyanomet-
hyl)bicyclo[2.2.1]heptan-1-yl)-4-methylbenzenesulfonamide
Trifluoroacetate Salt
[1203] Prepared according to the procedure described for Example
424, Step 8, utilizing
2-(4-aminobicyclo[2.2.1]heptan-1-yl)acetonitrile instead of
1-methyl-2-oxabicyclo[2.1.1]hexan-4-amine hydrochloride. LCMS
calculated for C.sub.21H.sub.24N.sub.7O.sub.2S (M+H).sup.+:
m/z=438.2; found: 438.1.
Example 431.
3-(4-Aminoimidazo[1,2-][1,2,4]triazin-7-yl)-N-(4-(2-hydroxypropan-2-yl)bi-
cyclo[2.2.1]heptan-1-yl)-4-methylbenzenesulfonamide
Trifluoroacetate Salt
##STR00619##
[1204] Step 1. 2-(4-Aminobicyclo[2.2.I]heptan-1-yl)propan-2-ol
Hydrochloride
##STR00620##
[1206] To a solution of methyl
4-(((benzyloxy)carbonyl)amino)bicyclo[2.2.1]heptane-1-carboxylate
(80 mg, 0.26 mmol, 430, Step 2) in THF (2.0 mL) at 0.degree. C. was
added methyllithium (0.99 mL, 1.58 mmol) dropwise. The reaction
mixture was allowed to warm to room temperature. After stirring for
2 h, the reaction mixture was heated to 70.degree. C. for 2 h. The
reaction mixture was cooled to 0.degree. C. and slowly quenched
with 1M HCl. The aqueous layer was washed with EtOAc and
concentrated in vacuo. The product was used without purification.
LCMS calculated for C.sub.10H.sub.20NO (M+H).sup.+: m/z=170.2;
found: 170.2.
Step 2.
3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-((1s,4s)-4-(2-hydro-
xypropan-2-yl)bicyclo[2.2.l]heptan-1-yl)-4-methylbenzenesulfonamide
Trifluoroacetate Salt
[1207] Prepared according to the procedure described for Example
424, Step 8, utilizing
2-(4-aminobicyclo[2.2.1]heptan-1-yl)propan-2-ol hydrochloride salt
instead of 1-methyl-2-oxabicyclo[2.1.1]hexan-4-amine hydrochloride
salt. LCMS calculated for C.sub.22H.sub.29N.sub.6O.sub.3S
(M+H).sup.+: m/z=457.2; found: 457.2.
Example 432.
3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(1-(1-hydroxyethyl)-2-oxab-
icyclo[2.2.2]octan-4-yl)-4-methylbenzenesulfonamide
Trifluoroacetate Salt (Racemic)
##STR00621##
[1208] Step 1. 1-(4-Amino-2-oxabicyclo[2.2.2]octan-1-yl)ethanol
Trifluoroacetate salt
##STR00622##
[1210] To a solution of tert-butyl
1-formyl-2-oxabicyclo[2.2.2]octan-4-ylcarbamate (30 mg, 0.12 mmol,
Advanced Chemblocks) in THF (1.0 mL) at 0.degree. C. was added
methylmagnesium bromide (0.12 mL, 0.35 mmol) and the reaction
mixture was allowed to warm to room temperature. The reaction
mixture was quenched with saturated NH.sub.4Cl and partitioned
between water and EtOAc. The layers were separated and the organic
layer was washed with brine, dried over MgSO.sub.4, filtered, and
concentrated. The residue was taken up in DCM (2.0 mL) and treated
with TFA (0.5 mL, 6.49 mmol). After stirring for 0.5 h, the
volatiles were removed in vacuo, the residue was taken up in 1:1
MeCN/H.sub.2O, and lyophilized. The residue was used without
purification. LCMS calculated for C.sub.9H.sub.18NO.sub.2
(M+H).sup.+: m/z=172.1; found: 172.1.
Step 2.
3-(4-aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(1-(1-hydroxyethyl)-
-2-oxabicyclo[2.2.2]octan-4-yl)-4-methylbenzenesulfonamide
Trifluoroacetate Salt
[1211] Prepared according to the procedure described for Example
424, Step 8, utilizing
1-(4-amino-2-oxabicyclo[2.2.2]octan-1-yl)ethanol trifluoroacetate
salt instead of 1-methyl-2-oxabicyclo[2.1.1]hexan-4-amine
hydrochloride. LCMS calculated for C.sub.21H.sub.27N.sub.6O.sub.4S
(M+H).sup.+: m/z=459.2; found: 459.2.
Example 433.
3-(4-Aminoimidazo[1,2-][1,2,4]triazin-7-yl)-N-(1-(hydroxymethyl)-2-oxabic-
yclo[2.2.2]octan-4-yl)-4-methylbenzenesulfonamide Trifluoroacetate
Salt
##STR00623##
[1212] Step 1. (4-Amino-2-oxabicyclo[2.2.2]octan-1-yl)methanol
Trifluoroacetate Salt
##STR00624##
[1214] To a solution of tert-butyl
1-formyl-2-oxabicyclo[2.2.2]octan-4-ylcarbamate (30 mg, 0.12 mmol,
Advanced Chemblocks) in EtOH (1.0 mL) at 0.degree. C. was added
sodium borohydride (22 mg, 0.59 mmol). The reaction mixture was
warmed to room temperature and stirred for 0.5 h. The reaction
mixture was diluted with EtOAc and water, and the layers were
separated. The organic layer was washed with brine, dried over
MgSO.sub.4, filtered, and concentrated. The residue was dissolved
in DCM (2.0 mL) and treated with TFA (0.5 mL, 6.49 mmol). After
stirring for 0.5 h, the volatiles were removed in vacuo, the
residue was dissolved in 1:1 MeCN/H.sub.2O, and lyophilized. The
product was used without purification. LCMS calculated for
C.sub.8H.sub.16NO.sub.2 (M+H).sup.+: m/z=158.1; found: 158.2.
Step 2.
3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(1-(hydroxymethyl)--
2-oxabicyclo[2.2.2]octan-4-yl)-4-methylbenzenesulfonamide
Trifluoracetate
[1215] Prepared according to the procedure described for Example
424, Step 8, utilizing
(4-amino-2-oxabicyclo[2.2.2]octan-1-yl)methanol trifluoroacetate
salt instead of 1-methyl-2-oxabicyclo[2.1.1]hexan-4-amine
hydrochloride salt. LCMS calculated for
C.sub.20H.sub.25N.sub.6O.sub.4S (M+H).sup.+: m/z=445.2; found:
445.2.
Example 434.
3-(4-Aminoimidazo[1,2-][1,2,4]triazin-7-yl)-4-methyl-N-(1-(morpholinometh-
yl)-2-oxabicyclo[2.2.2]octan-4-yl)benzenesulfonamide
Trifluoroacetate Salt
##STR00625##
[1216] Step 1.
1-(Morpholinomethyl)-2-oxabicyclo[2.2.2]octan-4-amine Hydrochloride
Salt
##STR00626##
[1218] To a solution of tert-butyl
1-formyl-2-oxabicyclo[2.2.2]octan-4-ylcarbamate (20 mg, 0.078 mmol,
Advanced Chemblocks) in THF (1.0 mL) was added morpholine (20
.mu.L, 0.24 mmol), sodium triacetoxyborohydride (50 mg, 0.24 mmol),
and 1 drop of AcOH. The reaction mixture was stirred at room
temperature overnight. The reaction mixture was quenched with
saturated NaHCO.sub.3 and extracted with EtOAc. The organic layer
was washed with brine, dried over MgSO.sub.4, filtered and
concentrated. The residue was purified by flash chromatography
(0-100% EtOAc/hexanes). The product was taken up in HCl (4
M/dioxane) (3 mL) and stirred at room temperature for 1 h. The
volatiles were removed in vacuo and the residue was used without
purification. LCMS calculated for C.sub.12H.sub.23N.sub.2O.sub.2
(M+H).sup.+: m/z=227.2; found: 227.1.
Step 2.
3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methyl-N-(1-(morpho-
linomethyl)-2-oxabicyclo[2.2.2]octan-4-yl)benzenesulfonamide
Trifluoroacetate Salt
[1219] Prepared according to the procedure described for Example
424, Step 8, utilizing
1-(morpholinomethyl)-2-oxabicyclo[2.2.2]octan-4-amine hydrochloride
salt instead of 1-methyl-2-oxabicyclo[2.1.1]hexan-4-amine
hydrochloride salt. LCMS calculated for
C.sub.24H.sub.32N.sub.7O.sub.4S (M+H).sup.+: m/z=514.2; found:
514.2.
Example 435.
3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(1-((3,3-difluoroazetidin--
1-yl)methyl)-2-oxabicyclo[2.2.2]octan-4-yl)-4-methylbenzenesulfonamide
Trifluoroacetate Salt
##STR00627##
[1221] Prepared according to the procedure described for Example
434, utilizing 3,3-difluoroazetidine hydrochloride instead of
morpholine in Step 1. LCMS calculated for
C.sub.23H.sub.28F.sub.2N.sub.7O.sub.3S (M+H).sup.+: m/z=520.2;
found: 520.2.
Example 436.
3-(4-aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(1-(difluoromethyl)-2-oxab-
icyclo[2.2.2]octan-4-yl)-4-methylbenzenesulfonamide
Trifluoroacetate Salt
##STR00628##
[1222] Step 1. 1-(Difluoromethyl)-2-oxabicyclo[2.2.2]octan-4-amine
Hydrochloride
##STR00629##
[1224] To a solution of tert-butyl
1-formyl-2-oxabicyclo[2.2.2]octan-4-ylcarbamate (30 mg, 0.12 mmol,
Advanced Chemblocks) in DCM (1.0 mL) was added diethylaminosulfur
trifluoride (47 .mu.L, 0.35 mmol). The reaction mixture was stirred
at room temperature overnight and was quenched with saturated
NaHCO.sub.3. The reaction mixture was diluted with DCM and water,
and the layers were separated. The organic layer was dried over
MgSO.sub.4, filtered, and concentrated. The residue was purified by
flash chromatography (0-20% EtOAc/hexanes) to afford the desired
product as a white solid. This solid was taken up in HCl (4
M/dioxane) (3.0 mL) and stirred at room temperature for 1 h. The
volatiles were removed in vacuo to afford the title compound (16
mg, 63%). LCMS calculated for C.sub.8H.sub.14F.sub.2NO (M+H).sup.+:
m/z=178.1; found: 178.1.
Step 2.
3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(1-(difluoromethyl)-
-2-oxabicyclo[2.2.2]octan-4-yl)-4-methylbenzenesulfonamide
Trifluoroacetate Salt
[1225] Prepared according to the procedure described for Example
424, Step 8, utilizing
1-(difluoromethyl)-2-oxabicyclo[2.2.2]octan-4-amine hydrochloride
instead of 1-methyl-2-oxabicyclo[2.1.1]hexan-4-amine hydrochloride.
LCMS calculated for C.sub.20H.sub.23F.sub.2N.sub.6O.sub.3S
(M+H).sup.+: m/z=465.1; found: 465.1.
Example 437.
3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methyl-N-(1-(2,2,2-trifluo-
ro-1-hydroxyethyl)-2-oxabicyclo[2.2.2]octan-4-yl)benzenesulfonamide
Trifluoroacetate Salt (Racemic)
##STR00630##
[1226] Step 1.
1-(4-Amino-2-oxabicyclo[2.2.2]octan-1-yl)-2,2,2-trifluoroethanol
Hydrochloride Salt
##STR00631##
[1228] A solution of tert-butyl
1-formyl-2-oxabicyclo[2.2.2]octan-4-ylcarbamate (54 mg, 0.21 mmol,
Advanced Chemblocks) and trifluoromethyltrimethylsilane (94 .mu.L,
0.64 mmol) in DMF (2.0 mL) was cooled to 0.degree. C. To this
solution was added cesium fluoride (96 mg, 0.64 mmol) and the
reaction mixture was stirred overnight at room temperature. The
reaction was quenched with saturated NaHCO.sub.3 and partitioned
between EtOAc and water. The layers were separated and the organic
layer was washed with brine, dried over MgSO.sub.4, filtered and
concentrated. The residue was taken up in HCl (4 M/dioxane) (2 mL)
and the solution was stirred at room temperature for 1 h. The
volatiles were removed in vacuo and the residue was used without
purification. LCMS calculated for C.sub.9H.sub.15F.sub.3NO.sub.2
(M+H).sup.+: m/z=226.1; found: 226.0.
Step 2.
3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methyl-N-(1-(2,2,2--
trifluoro-1-hydroxyethyl)-2-oxabicyclo[2.2.2]octan-4-yl)benzenesulfonamide
Trifluoroacetate Salt
[1229] Prepared according to the procedure described for Example
424, Step 8, utilizing
1-(4-amino-2-oxabicyclo[2.2.2]octan-1-yl)-2,2,2-trifluoroethanol
hydrochloride instead of 1-methyl-2-oxabicyclo[2.1.1]hexan-4-amine
hydrochloride. LCMS calculated for
C.sub.21H.sub.24F.sub.3N.sub.6O.sub.4S (M+H).sup.+: m/z=513.2;
found: 513.1.
Example 438.
3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(1-(hydroxy(phenyl)methyl)-
-2-oxabicyclo[2.2.2]octan-4-yl)-4-methylbenzenesulfonamide
Trifluoroacetate Salt (Racemic)
##STR00632##
[1230] Step 1.
(4-Amino-2-oxabicyclo[2.2.2]octan-1-yl)(phenyl)methanol
Hydrochloride Salt
##STR00633##
[1232] To a solution of tert-butyl
1-formyl-2-oxabicyclo[2.2.2]octan-4-ylcarbamate (25 mg, 98 .mu.mol)
in THF (1.0 mL) at 0.degree. C. was added phenylmagnesium bromide
(0.33 mL, 0.98 mmol). The reaction mixture was warmed to room
temperature and stirred overnight. The reaction was quenched with
saturated NH.sub.4Cl and extracted with EtOAc. The organic layer
was washed with brine, dried over MgSO.sub.4, and concentrated. The
residue was dissolved in HCl (4M/dioxane) (2 mL, 8.00 mmol) and
stirred at room temperature for 1 h. The volatiles were removed in
vacuo and the residue was used without purification. LCMS
calculated for C.sub.14H.sub.20NO.sub.2 (M+H).sup.+: m/z=234.1;
found: 234.2.
Step 2.
3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-(1-(hydroxy(phenyl)-
methyl)-2-oxabicyclo[2.2.2]octan-4-yl)-4-methylbenzenesulfonamide
Trifluoroacetate Salt (Racemic)
[1233] Prepared according to the procedure described for Example
424, Step 8, utilizing
(4-amino-2-oxabicyclo[2.2.2]octan-1-yl)(phenyl)methanol
hydrochloride instead of 1-methyl-2-oxabicyclo[2.1.1]hexan-4-amine
hydrochloride. LCMS calculated for C.sub.26H.sub.29N.sub.6O.sub.4S
(M+H).sup.+: m/z=521.2; found: 521.1.
Example 439.
3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methyl-N-(1-(1-methyl-1H-i-
midazol-2-yl)-2-oxabicyclo[2.2.2]octan-4-yl)benzenesulfonamide
Trifluoroacetate Salt
##STR00634##
[1234] Step 1. tert-butyl
1-(1H-imidazol-2-yl)-2-oxabicyclo[2.2.2]octan-4-ylcarbamate
##STR00635##
[1236] To a solution of tert-butyl
1-formyl-2-oxabicyclo[2.2.2]octan-4-ylcarbamate (50 mg, 0.20 mmol,
Advanced Chemblocks) in ammonia (7 N/MeOH) (1 mL, 7.0 mmol) was
added glyoxal (67 .mu.L, 0.59 mmol) and the reaction mixture was
stirred at room temperature overnight. The volatiles were removed
in vacuo and the residue was partitioned between EtOAc and water.
The layers were separated and the organic layer was washed with
brine, dried over MgSO.sub.4, filtered and concentrated. The
residue was purified by flash chromatography (0-15% MeOH/DCM) to
afford the title compound (24 mg, 42%). LCMS calculated for
C.sub.15H.sub.24N.sub.3O.sub.3 (M+H).sup.+: m/z=294.2; found:
294.2.
Step 2.
1-(1-Methyl-1H-imidazol-2-yl)-2-oxabicyclo[2.2.2]octan-4-amine
Hydrochloride Salt
##STR00636##
[1238] To a solution of tert-butyl
1-(1H-imidazol-2-yl)-2-oxabicyclo[2.2.2]octan-4-ylcarbamate (24 mg,
0.08 mmol) in acetonitrile (3.0 mL) was added potassium carbonate
(34 mg, 0.25 mmol), followed by methyl iodide (15 .mu.L, 0.25
mmol), and the reaction mixture was heated to 60.degree. C.
overnight. The reaction mixture was cooled to room temperature and
partitioned between water and EtOAc. The layers were separated and
the organic layer was washed with brine, dried over MgSO.sub.4,
filtered and concentrated. The residue was taken up in HCl
(4M/dioxane, 3.0 mL) and stirred at room temperature for 1 h. The
volatiles were removed in vacuo and the product was used without
purification. LCMS calculated for C.sub.11H.sub.18N.sub.3O
(M+H).sup.+: m/z=208.1; found: 208.1.
Step 3.
3-(4-aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methyl-N-(1-(1-meth-
yl-H-imidazol-2-yl)-2-oxabicyclo[2.2.2]octan-4-yl)benzenesulfonamide
Trifluoroacetate Salt
[1239] Prepared according to the procedure described for Example
424, Step 8, utilizing
1-(1-methyl-1H-imidazol-2-yl)-2-oxabicyclo[2.2.2]octan-4-amine
hydrochloride instead of 1-methyl-2-oxabicyclo[2.1.1]hexan-4-amine
hydrochloride. LCMS calculated for C.sub.23H.sub.27N.sub.8O.sub.3S
(M+H).sup.+: m/z=495.2; found: 495.3.
Example 440.
3-(4-Aminoimidazo[1,2-][1,2,4]triazin-7-yl)-4-methyl-N-(1-(oxazol-5-yl)-2-
-oxabicyclo[2.2.2]octan-4-yl)benzenesulfonamide Trifluoroacetate
Salt
##STR00637##
[1240] Step 1. 1-(Oxazol-5-yl)-2-oxabicyclo[2.2.2]octan-4-amine
Hydrochloride Salt
##STR00638##
[1242] To a solution of tert-butyl
1-formyl-2-oxabicyclo[2.2.2]octan-4-ylcarbamate (30 mg, 0.12 mmol,
Advanced Chemblocks) in methanol (1.0 mL) was added potassium
carbonate (49 mg, 0.35 mmol), followed by TosMIC (34 mg, 0.18
mmol), and the reaction mixture was heated to reflux overnight. The
reaction mixture was partitioned between water and EtOAc, and the
layers were separated. The organic layer was washed with brine,
dried over MgSO.sub.4, filtered and concentrated. The residue was
purified by flash chromatography (0-70% EtOAc/hexanes) to afford
the desired product as a white solid. This was taken up in HCl
(4M/dioxane, 2.0 mL) and stirred at room temperature for 1 h. The
volatiles were removed in vacuo to afford the title compound (18
mg, 66%). LCMS calculated for C.sub.10H.sub.15N.sub.2O.sub.2
(M+H).sup.+: m/z=195.1; found: 195.1.
Step 2.
3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methyl-N-(1-(oxazol-
-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl)benzenesulfonamide
Trifluoroacetate Salt
[1243] Prepared according to the procedure described for Example
424, Step 8, utilizing
1-(oxazol-5-yl)-2-oxabicyclo[2.2.2]octan-4-amine hydrochloride salt
instead of 1-methyl-2-oxabicyclo[2.1.1]hexan-4-amine hydrochloride
salt. LCMS calculated for C.sub.22H.sub.24N.sub.7O.sub.4S
(M+H).sup.+: m/z=482.2; found: 482.1.
Example 441.
3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-N-(1-(2-hydroxy-
propan-2-yl)-2-oxabicyclo[2.2.2]octan-4-yl)-4-methylbenzenesulfonamide
Trifluoroacetate Salt
##STR00639##
[1244] Step 1. tert-butyl
1-acetyl-2-oxabicyclo[2.2.2]octan-4-ylcarbamate
##STR00640##
[1246] To a solution of tert-butyl
1-(1-hydroxyethyl)-2-oxabicyclo[2.2.2]octan-4-ylcarbamate (213 mg,
0.79 mmol, 432, Step 1) in DCM (5 mL) at 0.degree. C. was added
sodium bicarbonate (198 mg, 2.36 mmol), followed by Dess-Martin
periodinane (499 mg, 1.18 mmol), and the reaction mixture was
allowed to warm to room temperature. After stirring for 1 h, TLC
indicated complete consumption of SM. The reaction mixture was
diluted with DCM, quenched with saturated Na.sub.2S.sub.2O.sub.3
and saturated NaHCO.sub.3. The suspension was vigorously stirred
until two clear layers were obtained. The layers were separated and
the organic layer was dried over MgSO.sub.4, filtered and
concentrated. The residue was purified by flash chromatography
(0-40% EtOAc/hexanes) to afford the product as a white solid (104
mg, 49%).
Step 2. 2-(4-Amino-2-oxabicyclo[2.2.2]octan-1-yl)propan-2-ol
hydrochloride Salt
##STR00641##
[1248] To a solution of tert-butyl
1-acetyl-2-oxabicyclo[2.2.2]octan-4-ylcarbamate (30 mg, 0.11 mmol)
in THF (2.0 mL) at 0.degree. C. was added methylmagnesium bromide
(0.19 mL, 0.56 mmol). The reaction mixture was allowed to warm to
room temperature and stir for 1 h. The reaction was quenched with
water and extracted with EtOAc. The organic extracts were washed
with brine, dried over MgSO.sub.4, filtered, and concentrated. The
residue was taken up in HCl (4M/dioxane, 3 mL) and stirred at room
temperature for 1 h. The volatiles were removed in vacuo and the
residue was used without purification. LCMS calculated for
C.sub.10H.sub.20NO.sub.2 (M+H).sup.+: m/z=186.1; found: 186.2.
Step 3.
3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-N-(1-(2--
hydroxypropan-2-yl)-2-oxabicyclo[2.2.2]octan-4-yl)-4-methylbenzenesulfonam-
ide Trifluoroacetate Salt
[1249] Prepared according to the procedure described for Example
428, utilizing 2-(4-amino-2-oxabicyclo[2.2.2]octan-1-yl)propan-2-ol
hydrochloride salt instead of
(4-amino-2-oxabicyclo[2.1.1]hexan-1-yl)methanol. LCMS calculated
for C.sub.24H.sub.29F.sub.3N.sub.5O.sub.4S (M+H).sup.+: m/z=540.2;
found: 540.1.
Example 442.
3-(4-Aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-((1s,4s)-4-hydroxybicyclo[-
2.2.1]heptan-1-yl)-4-methylbenzenesulfonamide Trifluoroacetate
Salt
##STR00642##
[1250] Step 1. 4-Hydroxybicyclo[2.2.I]heptane-1-carboxylic Acid
##STR00643##
[1252] To a solution of methyl
4-hydroxybicyclo[2.2.1]heptane-1-carboxylate (487 mg, 2.86 mmol,
Advanced Chemblocks, L13452) in MeOH (5 mL) was added sodium
hydroxide (572 mg, 14.3 mmol) in water (5.0 mL) and the reaction
mixture was stirred at room temperature. After 1 h, the reaction
mixture was acidified with 1 M HCl to pH 1 and extracted with three
portions of EtOAc. The organic extracts were washed with brine,
dried over MgSO.sub.4, filtered and concentrated to afford a tan
solid (257 mg, 58%) that was used without purification.
Step 2. 4-aminobicyclo[2.2.I]heptan-1-ol hydrochloride Salt
##STR00644##
[1254] To a solution of 4-hydroxybicyclo[2.2.1]heptane-1-carboxylic
acid (257 mg, 1.65 mmol) and triethylamine (0.28 mL, 1.98 mmol) in
toluene (6.0 mL) was added diphenylphosphoryl azide (0.43 mL, 1.98
mmol) and the reaction mixture was heated to reflux for 2 h. The
reaction mixture was diluted with EtOAc, washed with water and
brine, dried over MgSO.sub.4 and concentrated. The residue was
taken up in a 1:1 mixture of AcOH and 15% HCl (1 mL each) and
stirred at room temperature for 1 h. The reaction mixture was
washed with EtOAc and the aqueous layer was concentrated to dryness
to afford the title compound, which was used without
purification.
Step 3.
3-(4-aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-N-((1s,4s)-4-hydroxyb-
icyclo[2.2.l]heptan-1-yl)-4-methylbenzenesulfonamide
Trifluoroacetate Salt
[1255] Prepared according to the procedure described for Example
424, Step 8, utilizing 4-aminobicyclo[2.2.1]heptan-1-ol
hydrochloride salt instead of
1-methyl-2-oxabicyclo[2.1.1]hexan-4-amine hydrochloride salt. LCMS
calculated for C.sub.19H.sub.23N.sub.6O.sub.3S (M+H).sup.+:
m/z=415.1; found: 415.2.
Example 443.
3-(4-Amino-2-methylimidazo[1,2-][1,2,4]triazin-7-yl)-N-(4-hydroxybicyclo[-
2.2.1]heptan-1-yl)-4-methylbenzenesulfonamide Trifluoroacetate
Salt
##STR00645##
[1257] Prepared according to the procedure described for Example
442, utilizing
3-(4-amino-2-methylimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methylb-
enzene-1-sulfonyl chloride (4N Me SO.sub.2Cl) instead of
3-(4-aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methylbenzene-1-sulfonyl
chloride in Step 3. LCMS calculated for
C.sub.20H.sub.25N.sub.6O.sub.3S (M+H).sup.+: m/z=429.2; found:
429.1.
Example 444.
3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-N-(4-hydroxybic-
yclo[2.2.1]heptan-1-yl)-4-methylbenzenesulfonamide Trifluoroacetate
Salt
##STR00646##
[1259] Prepared according to the procedure described for Example
442, utilizing
3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-met-
hylbenzene-1-sulfonyl chloride (Example 472, Step 8) instead of
3-(4-aminoimidazo[1,2-f][1,2,4]triazin-7-yl)-4-methylbenzene-1-sulfonyl
chloride (Example 424, Step 7) in Step 3. LCMS calculated for
C.sub.21H.sub.23F.sub.3N.sub.5O.sub.3S (M+H).sup.+: m/z=482.1;
found: 482.1.
Example 445.
8-Amino-3-(5-(N-((3,3-difluorocyclobutyl)methyl)sulfamoyl)-2-methylphenyl-
)-N-methylimidazo[1,2-a]pyrazine-6-carboxamide Trifluoroacetate
Salt
##STR00647##
[1260] Step 1.
N-(3,3-difluorocyclobutyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxabor-
olan-2-yl)benzenesulfonamide
##STR00648##
[1262] To a solution of 3-bromo-4-methylbenzenesulfonyl chloride
(300 mg, 1.11 mmol) and i-Pr.sub.2NEt (0.58 mL, 3.33 mmol in DCM
(11 mL) at 0.degree. C. was added DMAP (6.80 mg, 56 .mu.mol) and
(3,3-difluorocyclobutyl)methanamine hydrochloride (193 mg, 1.22
mmol) in one portion. After stirring at 0.degree. C. for 2 h, the
reaction was quenched by adding saturated NaHCO.sub.3. The layers
were separated and the organic layer was dried over MgSO.sub.4,
filtered, and concentrated. The residue was used without
purification.
[1263] A mixture of
3-bromo-N-((3,3-difluorocyclobutyl)methyl)-4-methylbenzenesulfonamide
(338 mg, 0.95 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (254
mg, 1.0 mmol), potassium acetate (309 mg, 3.15 mmol), and
Dichlorobis(triphenylphosphine)-palladium(II) (27 mg, 38 .mu.mol)
in THF (2.7 mL) was degassed with N.sub.2 for 5 min. The mixture
was heated in a microwave at 140.degree. C. for 20 minutes. The
reaction mixture was diluted with EtOAc and filtered through
Celite.RTM., rinsing with EtOAc. The filtrate was washed with water
and then brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated. Purification via silica gel chromatography (10-50%
EtOAc/DCM) afforded the desired product as a yellow oil. LCMS
calculated for C.sub.18H.sub.27BF.sub.2NO.sub.4S (M+H).sup.+:
m/z=402.2; found: 402.1.
Step 2.
3-(8-Amino-6-bromoimidazo[1,2-a]pyrazin-3-yl)-N-((3,3-difluorocycl-
obutyl)methyl)-4-methylbenzenesulfonamide
##STR00649##
[1265] A mixture of 6-bromo-3-iodoimidazo[1,2-a]pyrazin-8-amine
(120 mg, 0.35 mmol, 3N Br I),
N-((3,3-difluorocyclobutyl)methyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2--
dioxaborolan-2-yl)benzenesulfonamide (156 mg, 0.389 mmol), and
tetrakis(triphenylphosphine)palladium(0) (24.96 mg, 0.022 mmol) in
ethanol (4 mL)/2.0 M sodium carbonate in water (0.35 mL) was
degassed for 5 min with N.sub.2. The reaction mixture was then
heated in a microwave reactor at 130.degree. C. for 20 min. The
reaction mixture was diluted with MeOH and filtered through a plug
of Celite.COPYRGT.. The filtrate was concentrated and the residue
was purified by flash chromatography (0-100% EtOAc/hexanes) to
afford the title compound (170 mg, 99%). LCMS calculated for
C.sub.18H.sub.19BrF.sub.2N.sub.5O.sub.2S (M+H).sup.+: m/z=486.0;
found: 486.0.
Step 3. Methyl
8-amino-3-(5-(N-((3,3-difluorocyclobutyl)methyl)sulfamoyl)-2-methylphenyl-
)imidazo[1,2-a]pyrazine-6-carboxylate
##STR00650##
[1267] In a 40 mL vial, a solution of
3-(8-amino-6-bromoimidazo[1,2-a]pyrazin-3-yl)-N-((3,3-difluorocyclobutyl)-
methyl)-4-methylbenzenesulfonamide (200 mg, 0.41 mmol),
dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II)
dichloromethane adduct (34 mg, 41 .mu.mol), and triethylamine (0.23
mL, 1.65 mmol) in methanol (10 mL) was saturated with CO by
bubbling the gas through the solution for 5 min. The vessel was
heated to 60.degree. C. under 1 atm of CO for 5 h. Upon standing at
room temperature overnight, the product precipitated. The
suspension was treated with ether and cooled in an ice bath. The
solid was filtered, washed with ether, and air dried to yield the
desired product as a tan solid (84 mg, 44%). LCMS calculated for
C.sub.20H.sub.22F.sub.2N.sub.5O.sub.4S (M+H).sup.+: m/z=466.1;
found: 466.2.
Step 4.
8-Amino-3-(5-(N-((3,3-difluorocyclobutyl)methyl)sulfamoyl)-2-methy-
lphenyl)-N-methylimidazo[1,2-a]pyrazine-6-carboxamide
Trifluoroacetate Salt
[1268] To a solution of methyl
8-amino-3-(5-(N-((3,3-difluorocyclobutyl)methyl)sulfamoyl)-2-methylphenyl-
)imidazo[1,2-a]pyrazine-6-carboxylate (15 mg, 0.032 mmol) in THF
(2.0 mL) at rt was added methanamine (0.161 mL, 0.322 mmol), and
trimethylaluminum (0.081 mL, 0.161 mmol) (2M in toluene). The
resultant solution was heated at 80.degree. C. for 3 h. After
cooling to rt, MeOH (2 mL) was added. The mixture was stirred at rt
for 1 h and filtered through Celite.RTM.. The filtrate was
concentrated under vacuum. The residue was dissolved in MeOH (5 mL)
and purified by pH 2 prep-LCMS to afford the desired product. LCMS
calculated for C.sub.20H.sub.23F.sub.2N.sub.6O.sub.3S (M+H).sup.+:
m/z=465.1; found: 465.1.
[1269] Example 446 listed in following table was prepared
analogously to Example 445 utilizing the appropriate commercially
available amine:
##STR00651##
TABLE-US-00020 Ex. No. Name R LCMS 446
8-amino-N-cyclobutyl-3-(5-(N-((3,3-
difluorocyclobutypmethyl)sulfamoyl)- 2-methylphenypimidazo [1,2-
a]pyrazine-6-carboxamide trifluoroacetate salt ##STR00652##
505.2
Example 447.
8-Amino-3-(5-(N-(3,3-difluorocyclobutyl)sulfamoyl)-2-methylphenyl)-N-meth-
ylimidazo[1,2-a]pyrazine-6-carboxamide Trifluoroacetate Salt
##STR00653##
[1271] Prepared according to the procedure described for Example
445 utilizing 3,3-difluorocyclobutanamine hydrochloride salt
instead of (3,3-difluorocyclobutyl)methanamine hydrochloride salt
in Step 1. LCMS calculated for
C.sub.19H.sub.21F.sub.2N.sub.6O.sub.3S (M+H).sup.+: m/z=451.1;
found: 451.1.
[1272] Example 448 in the following table was prepared analogously
to Example 447 utilizing the appropriate commercially available
amine:
##STR00654##
TABLE-US-00021 Ex. No. Name R LCMS 448
8-amino-N-cyclobutyl-3-(5-(N- (3,3-difluorocyclobutyl)sulfamoyl)-
2-methylphenyl)imidazo[1,2-a] pyrazine-6-carboxamide
trifluoroacetate salt ##STR00655## 491.1
Example 449.
8-Amino-3-(5-(N-((3S,6R)-6-(cyanomethyl)tetrahydro-2H-pyran-3-yl)sulfamoy-
l)-2-methylphenyl)-N-methylimidazo[1,2-a]pyrazine-6-carboxamide
Trifluoroacetate Salt
##STR00656##
[1274] Prepared according to the procedure described for Example
445 utilizing
2-((2R,5S)-5-aminotetrahydro-2H-pyran-2-yl)acetonitrile instead of
(3,3-difluorocyclobutyl)methanamine hydrochloride in Step 1. LCMS
calculated for C.sub.22H.sub.26N.sub.7O.sub.4S (M+H).sup.+:
m/z=484.2; found: 484.1.
[1275] Examples 450 and 451 in the following table were prepared
analogously to Example 449 utilizing the appropriate commercially
available amine:
##STR00657##
TABLE-US-00022 Ex. No. Name R LCMS 450 8-amino-3-(5-(N-((3S,6R)-6-
(cyanomethyl)tetrahydro-2H- pyran-3-yl)sulfamoyl)-2-
methylphenyl)-N- cyclobutylimidazo[1,2- a]pyrazine-6-carboxamide
trifluoroacetate salt ##STR00658## 524.2 451
8-amino-3-(5-(N-((3S,6R)-6- (cyanomethyl)tetrahydro-2H-
pyran-3-yl)sulfamoyl)-2- methylphenyl)-N-(3,3-
difluorocyclobutyl)imidazo[1,2- a]pyrazine-6-carboxamide
trifluoroacetate salt ##STR00659## 560.2
Example 452.
8-Amino-N-(4-(diethylamino)butyl)-3-(2-methyl-5-(methylsulfonyl)phenyl)im-
idazo[1,2-a]pyrazine-6-carboxamide Trifluoroacetate Salt
##STR00660##
[1277] To a solution of methyl
8-amino-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazine-6-car-
boxylate (15 mg, 42 .mu.mol, Example 458, Step 1) in THF (1.0 mL)
at room temperature was added N,N-diethylbutane-1,4-diamine (80 mg,
0.41 mmol), and trimethylaluminum (0.10 mL, 0.21 mmol) (2 M in
toluene). The resultant solution was heated at 80.degree. C. for 3
h. After cooling to room temperature, MeOH (2 mL) was added. The
mixture was stirred at room temperature for 1 h and filtered
through Celite*. The filtrate was concentrated under vacuum. The
residue was dissolved in MeOH (5 mL) and purified by pH 2 prep-LCMS
to afford the desired product. LCMS calculated for
C.sub.23H.sub.33N.sub.6O.sub.3S (M+H).sup.+: m/z=473.2; found:
473.2.
[1278] The compounds listed in the following table were prepared
analogously to Example 452 utilizing the appropriate commercially
available amine:
##STR00661##
TABLE-US-00023 Ex. No. Name R LCMS 453
8-amino-N-(2-(1-methyl-1H-pyrazol-4-yl)
ethyl)-3-(2-methyl-5-(methylsulfonyl)phenyl)
imidazo[1,2-a]pyrazine-6-carboxamide trifluoroacetate salt
##STR00662## 454.1 454 8-amino-N-(5-(furan-2-yl)-1H-pyrazol-3-
yl)-3-(2-methyl-5-(methylsulfonyl)phenyl)
imidazo[1,2-a]pyrazine-6-carboxamide trifluoroacetate salt
##STR00663## 478.0 455 8-amino-3-(2-methyl-5-(methylsulfonyl)
phenyl)-N-(5-(4-methylpiperadzin-1-yl)
pyridin-2-yl)imidazo[1,2-a]pyrazine-6- carboxamide trifluoroacetate
salt ##STR00664## 521.3 456 8-amino-3-(2-methyl-5-(methylsulfonyl)
phenyl)-N-((4-(trifluoromethyl)cyclohexyl)
methyl)imidazo[1,2-a]pyrazine-6-carboxamide trifluoroacetate salt
(1:1 cis/trans isomers) ##STR00665## 510.1 457
N-(3-(1H-pyrazol-1-yl)propyl)-8-amino-3-
(2-methyl-5-(methylsulfonyl)phenyl)imidazo
[1,2-a]pyrazine-6-carboxamide trifluoroacetate salt ##STR00666##
454.1
Example 458.
8-Amino-N-(1-(2-methoxyethyl)piperidin-3-yl)-3-(2-methyl-5-(methylsulfony-
l)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide Trifluoroacetate
Salt
##STR00667##
[1279] Step 1. Methyl
8-amino-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazine-6-car-
boxylate
##STR00668##
[1281] In a 40 mL vial, a solution of
6-bromo-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-8-amin-
e (400 mg, 1.05 mmol),
Dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II)
dichloromethane adduct (86 mg, 0.11 mmol), and triethylamine (0.59
mL, 4.20 mmol) in methanol (8 mL) was saturated with CO by bubbling
the gas through the solution for 5 min. The vessel was heated to
60.degree. C. under 1 atm of CO for 5 h. The volatiles were removed
in vacuo and the resulting solid was suspended in EtOAc, filtered,
washed with additional EtOAc, and air dried to yield the desired
product as a light brown solid. LCMS calculated for
C.sub.1-6H.sub.17N.sub.4O.sub.4S (M+H).sup.+: m/z=361.1; found:
361.1.
Step 2.
8-Amino-3-(2-methyl-5-(methylsulfonyl)phenyl)-N-(piperidin-3-yl)im-
idazo[1,2-a]pyrazine-6-carboxamide Trifluoroacetate Salt
##STR00669##
[1283] To a solution of methyl
8-amino-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazine-6-car-
boxylate (100 mg, 0.28 mmol) in THF (3.0 mL) at room temperature
was added tert-butyl 3-aminopiperidine-1-carboxylate (0.19 mL, 0.83
mmol), and trimethylaluminum (2M/toluene, 0.42 mL, 0.83 mmol). The
resultant solution was heated at 80.degree. C. for 3 h. After
cooling to room temperature, MeOH (2 mL) was added. The mixture was
stirred at room temperature for 1 h and filtered through
Celite.RTM.. The filtrate was concentrated under vacuum. The
residue was dissolved in DCM (3 mL) and trifluoroacetic acid (2 mL)
was added. After stirring for 0.5 h, the volatiles were removed in
vacuo and the residue was used without purification. LCMS
calculated for C.sub.20H.sub.25N.sub.6O.sub.3S (M+H).sup.+:
m/z=429.2; found: 429.1.
Step 3.
8-amino-N-(1-(2-methoxyethyl)piperidin-3-yl)-3-(2-methyl-5-(methyl-
sulfonyl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide
Trifluoroacetate Salt
[1284] To a solution of
8-Amino-3-(2-methyl-5-(methylsulfonyl)phenyl)-N-(piperidin-3-yl)imidazo[1-
,2-a]pyrazine-6-carboxamide trifluoroacetate salt (15 mg, 28
.mu.mol) in acetonitrile (1.0 mL) was added potassium carbonate (12
mg, 83 .mu.mol), followed by 2-bromoethyl methyl ether (6 .mu.l, 83
.mu.mol), and the reaction mixture was heated to 60.degree. C.
overnight. No conversion was observed so the temperature was
increased to 90.degree. C. for a further 24 h. There was still no
conversion so several equivalents of cesium carbonate and excess
electrophile were added. Heating was continued at 90.degree. C.
overnight. Full conversion was observed by LCMS. The reaction
mixture was partitioned between water and EtOAc, and the layers
were separated. The organic layer was washed with brine, dried over
MgSO.sub.4, filtered and concentrated. The residue was purified by
prep HPLC (pH 2). LCMS calculated for
C.sub.23H.sub.31N.sub.6O.sub.4S (M+H).sup.+: m/z=487.2; found:
487.2.
Example 459.
8-Amino-N-(1-(cyanomethyl)piperidin-3-yl)-3-(2-methyl-5-(methylsulfonyl)p-
henyl)imidazo[1,2-a]pyrazine-6-carboxamide Trifluoroacetate
Salt
##STR00670##
[1286] Prepared according to the procedure described for Example
458, utilizing bromoacetonitrile instead of 2-bromoethyl methyl
ether. LCMS calculated for C.sub.22H.sub.26N.sub.7O.sub.3S
(M+H).sup.+: m/z=468.2; found: 468.1.
Example 460.
8-Amino-N-(1-(2-hydroxyethyl)piperidin-3-yl)-3-(2-methyl-5-(methylsulfony-
l)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide Trifluoroacetate Salt
(Racemic)
##STR00671##
[1288] Prepared according to the procedure described for Example
458, utilizing 2-bromoethanol instead of 2-bromoethyl methyl ether.
LCMS calculated for C.sub.22H.sub.29N.sub.6O.sub.4S (M+H).sup.+:
m/z=473.2; found: 473.1.
Example 461. Methyl
3-(8-amino-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazine-6--
carboxamido)piperidine-1-carboxylate Trifluoroacetate Salt
##STR00672##
[1290] To a solution of
8-amino-3-(2-methyl-5-(methylsulfonyl)phenyl)-N-(piperidin-3-yl)imidazo[1-
,2-a]pyrazine-6-carboxamide trifluoroacetate salt (12 mg, 22
.mu.mol, Example 458, Step 1) and DIPEA (19 .mu.L, 0.11 mmol) in
acetonitrile (1.0 mL) was added methyl chloroformate (9 .mu.L, 0.11
mmol) at 0.degree. C., and the reaction mixture was allowed to warm
to room temperature. After stirring for 1 h, the reaction mixture
was diluted with MeOH and purified by prep HPLC (pH 2). LCMS
calculated for C.sub.22H.sub.27N.sub.6O.sub.5S (M+H).sup.+:
m/z=487.2; found: 487.2.
Example 462.
8-Amino-3-(2-methyl-5-(methylsulfonyl)phenyl)-N-(1-(methylsulfonyl)piperi-
din-3-yl)imidazo[1,2-a]pyrazine-6-carboxamide Trifluoroacetate
Salt
##STR00673##
[1292] Prepared according to the procedure described for Example
461, utilizing methanesulfonyl chloride instead of methyl
chloroformate. LCMS calculated for
C.sub.21H.sub.27N.sub.6O.sub.5S.sub.2 (M+H).sup.+: m/z=507.1;
found: 507.1.
Example 463.
3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-((1r,4r)-4-hydroxy-4-methy-
lcyclohexyl)-4-methylbenzenesulfonamide
##STR00674##
[1293] Step 1.
N-((1r,4r)-4-Hydroxy-4-methylcyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl--
1,3,2-dioxaborolan-2-yl)benzenesulfonamide
##STR00675##
[1295] The title compound was synthesized according to experimental
procedures analogous to the synthesis of Example 1, steps 1 and 2
substituting (1r,4r)-4-amino-1-methylcyclohexan-1-ol for
trans-4-aminocyclohexanol in step 1. LCMS for
C.sub.20H.sub.32BNO.sub.5S (M+H).sup.+: calculated m/z=410.2; found
410.1.
Step 2.
3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-((1r,4r)-4-hydroxy--
4-methylcyclohexyl)-4-methylbenzenesulfonamide
[1296] The title compound was synthesized according to experimental
procedures analogous to the synthesis of Example 39, substituting
N-((1r,
4r)-4-hydroxy-4-methylcyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-d-
ioxaborolan-2-yl)benzenesulfonamide for
N-(trans-4-hydroxycyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxa-
borolan-2-yl)benzenesulfonamide. .sup.1H NMR (600 MHz,
d.sub.6-DMSO) .delta. 8.33 (br s, 1H), 8.25 (br s, 1H), 8.07 (s,
1H), 7.93 (d, J=1.9 Hz, 1H), 7.83-7.76 (m, 2H), 7.59 (t, J=8.0 Hz,
2H), 4.12 (s, 1H), 3.10 (s, 1H), 2.34 (s, 3H), 1.60 (m, 2H), 1.49
(m, 2H), 1.27 (m, 4H), 1.05 (s, 3H) LCMS for
C.sub.19H.sub.24N.sub.6O.sub.3S (M+H).sup.+: calculated m/z=417.2;
found 417.1.
Example 464.
(R)-3-(5-((3-Aminopiperidin-1-yl)sulfonyl)-2-methylphenyl)-6-(trifluorome-
thyl)imidazo[1,2-a]pyrazin-8-amine tris(2,2,2-trifluoroacetate)
##STR00676##
[1297] Step 1. Tert-Butyl
(R)-(1-((3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-meth-
ylphenyl)sulfonyl)piperidin-3-yl)carbamate
##STR00677##
[1299] The desired compound was prepared according to the procedure
of Example 466, step 2, using
3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylbenzene-
sulfonyl chloride and tert-butyl (R)-piperidin-3-ylcarbamate
[Combi-Blocks, AM-1743] as the starting materials. LCMS for
C.sub.24H.sub.30F.sub.3N.sub.6O.sub.4S (M+H).sup.+: m/z=555.2;
Found: 555.3.
Step 2.
(R)-3-(5-((3-Aminopiperidin-1-yl)sulfonyl)-2-methylphenyl)-6-(trif-
luoromethyl)imidazo[1,2-a]pyrazin-8-amine
tris(2,2,2-trifluoroacetate)
[1300] A solution of tert-butyl
(R)-(1-((3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-meth-
ylphenyl)sulfonyl)piperidin-3-yl)carbamate (0.019 g, 0.034 mmol) in
dichloromethane (0.86 mL) was treated with TFA (0.86 mL) and
stirred for 1 h. The reaction mixture was concentrated to a
residue. Purification by preparative LCMS (XBridge C18 Column,
eluting with a gradient of acetonitrile in water with 0.1%
trifluoroacetic acid, at flow rate of 60 mL/min) gave the desired
product (22 mg, 79%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
8.08-7.89 (m, 4H), 7.83 (s, 1H), 7.82-7.59 (m, 6H), 3.37 (d, J=11.2
Hz, 1H), 3.34-3.23 (m, 1H), 3.19-3.01 (m, 1H), 2.98-2.72 (m, 2H),
2.30 (s, 3H), 1.87-1.70 (m, 2H), 1.65-1.49 (m, 1H), 1.49-1.31 (m,
1H). LCMS for C.sub.19H.sub.22F.sub.3N.sub.6O.sub.2S (M+H).sup.+:
m/z=455.1; Found: 455.1.
Example 465.
5-(8-Amino-6-methylimidazo[1,2-a]pyrazin-3-yl)-N-((3R,6S)-6-(2-hydroxypro-
pan-2-yl)tetrahydro-2H-pyran-3-yl)-2,4-dimethylbenzenesulfonamide
##STR00678##
[1301] Step 1. Methyl
(2S,5R)-5-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-carboxylate
##STR00679##
[1303] A solution of
(2S,5R)-5-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-carboxylic
acid (0.199 g, 0.811 mmol) [Advanced ChemBlocks, I-9006] in
methanol (1.62 mL) at 0.degree. C. was treated with
(trimethylsilyl)diazomethane solution in diethyl ether (0.811 mL,
1.62 mmol) and stirred for 2 h. The reaction mixture was
concentrated to give the desired product (210 mg, 100%) as a white
solid that was used without further purification. LCMS for
C.sub.12H.sub.21NO.sub.5Na (M+Na).sup.+: m/z=282.1; Found:
282.0.
Step 2. Tert-Butyl
((3R,6S)-6-(2-hydroxypropan-2-yl)tetrahydro-2H-pyran-3-yl)carbamate
##STR00680##
[1305] A solution of methyl
(2S,5R)-5-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-carboxylate
(0.250 g, 0.964 mmol) in tetrahydrofuran (7.42 mL) at 0.degree. C.
was treated with methylmagnesium bromide (3.0 M in ether) (1.61 mL,
4.82 mmol) dropwise, and stirred at room temperature for 2 h. The
reaction mixture was cooled to 0.degree. C., quenched with
saturated ammonium chloride solution (20 mL), and extracted with
ethyl acetate. The organic layer was separated, dried over sodium
sulfate, filtered, and concentrated to give a crude residue.
Purification by flash column chromatography using ethyl acetate in
hexanes (0%-60%) gave the desired product (133 mg, 53.2%) as a
white solid. LCMS for C.sub.13H.sub.25NO.sub.4Na (M+Na).sup.+:
m/z=282.2; Found: 282.2.
Step 3. 2-((2S,5R)-5-Aminotetrahydro-2H-pyran-2-yl)propan-2-ol
Hydrochloride
##STR00681##
[1307] A solution of tert-butyl
((3R,6S)-6-(2-hydroxypropan-2-yl)tetrahydro-2H-pyran-3-yl)carbamate
(0.133 g, 0.513 mmol) in dioxane (1.03 mL) was treated with 4 M HCl
in dioxane (3.85 mL, 15.4 mmol) and stirred for 3 h. The reaction
mixture was concentrated and reconcentrated from acetonitrile
(2.times.) to give the desired product (103 mg, quantitative) as a
white solid that was used without further purification. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 7.99 (s, 3H), 4.24 (br s, 1H), 4.01
(d, J=8.0 Hz, 1H), 3.22 (t, J=10.7 Hz, 1H), 3.08-2.97 (m, 1H), 2.93
(d, J=10.8 Hz, 1H), 2.13-1.99 (m, 1H), 1.87-1.69 (m, 1H), 1.55-1.41
(m, 1H), 1.41-1.24 (m, 1H), 1.06 (s, 3H), 1.00 (s, 3H).
Step 4.
5-Bromo-N-((3R,6S)-6-(2-hydroxypropan-2-yl)tetrahydro-2H-pyran-3-y-
l)-2,4-dimethylbenzenesulfonamide
##STR00682##
[1309] The desired compound was prepared according to the procedure
of example 1, step 1, using 5-bromo-2,4-dimethylbenzenesulfonyl
chloride and 2-((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)propan-2-ol
hydrochloride as the starting materials. LCMS for
C.sub.16H.sub.24BrNO.sub.4SNa (M+Na).sup.+: m/z=428.1, 430.0;
Found: 428.0, 430.0.
Step 5.
N-((3R,6S)-6-(2-Hydroxypropan-2-yl)tetrahydro-2H-pyran-3-yl)-2,4-d-
imethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide
##STR00683##
[1311] The desired compound was prepared according to the procedure
of example 1, step 2, using
5-bromo-N-((3R,6S)-6-(2-hydroxypropan-2-yl)tetrahydro-2H-pyran-3-yl)-2,4--
dimethylbenzenesulfonamide as the starting material. LCMS for
C.sub.22H.sub.36BNO.sub.6SNa (M+Na).sup.+: m/z=476.2; Found:
476.2.
Step 6.
5-(8-Amino-6-methylimidazo[1,2-a]pyrazin-3-yl)-N-((3R,6S)-6-(2-hyd-
roxypropan-2-yl)tetrahydro-2H-pyran-3-yl)-2,4-dimethylbenzenesulfonamide
[1312] The desired compound was prepared according to the procedure
of example 1, step 3, using
3-iodo-6-methylimidazo[1,2-a]pyrazin-8-amine and
N-((3R,6S)-6-(2-hydroxypropan-2-yl)tetrahydro-2H-pyran-3-yl)-2,4-dimethyl-
-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide
as the starting materials. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 7.83 (d, J=7.2 Hz, 1H), 7.74 (s, 1H), 7.57 (s, 1H), 7.48
(s, 1H), 7.00 (s, 1H), 6.95 (s, 2H), 4.15 (s, 1H), 3.76-3.60 (m,
1H), 3.02-2.89 (m, 1H), 2.84 (d, J=10.4 Hz, 1H), 2.61 (s, 3H), 2.18
(s, 3H), 2.13 (s, 3H), 1.81-1.55 (m, 2H), 1.45-1.27 (m, 1H),
1.27-1.09 (m, 2H), 1.00 (s, 3H), 0.93 (s, 3H). LCMS for
C.sub.23H.sub.32N.sub.5O.sub.4S (M+H).sup.+: m/z=474.2; Found:
474.2.
Example 466.
3-(4-Amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-N-((3S,6-
R)-6-(cyanomethyl)tetrahydro-2H-pyran-3-yl)-5-fluoro-4-methylbenzenesulfon-
amide
##STR00684##
[1313] Step 1. 3-Bromo-5-fluoro-4-methylbenzenesulfonyl
Chloride
##STR00685##
[1315] A round-bottom flask was charged with water (80 mL) and
placed in an ice bath. To this was added thionyl chloride (13.2 mL,
180 mmol) over 35 min using an addition funnel. The reaction
mixture was warmed to room temperature with the aid of a room
temperature water bath, treated with copper(I) chloride (0.194 g,
1.96 mmol), and placed in a brine-ice bath. Concurrently in a
separate round-bottom flask, 3-bromo-5-fluoro-4-methylaniline (8.00
g, 39.2 mmol) [Oxchem, AX8258142] was added dropwise to
concentrated hydrochloric acid (98 mL) (the aniline was melted
using a 50.degree. C. oil bath before addition) which gave a
free-flowing but thick slurry. The reaction mixture was placed in a
brine-ice bath and the slurry became thicker but stirring was
maintained with a very large stir bar. The reaction mixture was
treated with a solution of sodium nitrite (2.98 g, 43.1 mmol) in
water (5.58 mL) over 5 mins at -3 to 0.degree. C. which led to
dissolution of most of the solids and a much thinner orange slurry.
After stirring for 5 mins, the reaction mixture was added to the
chilled thionyl chloride solution dropwise in portions by pipette
over 15 mins with gas evolution observed and temperature ranging
between -7 to -6.degree. C. The reaction mixture was stirred for
2.5 h, warmed to room temperature and stirred for 1 hr. The
reaction mixture was diluted with water (250 mL) and extracted with
ethyl acetate (3.times.200 mL). The combined organic extracts were
washed with brine (100 mL), dried with magnesium sulfate, filtered,
and concentrated to give the desired product (9.79 g, 87%) as an
amber oil that was used without further purification.
Step 2.
3-bromo-N-((3S,6R)-6-(cyanomethyl)tetrahydro-2H-pyran-3-yl)-5-fluo-
ro-4-methylbenzenesulfonamide
##STR00686##
[1317] A solution of
2-((2R,5S)-5-aminotetrahydro-2H-pyran-2-yl)acetonitrile
hydrochloride/2-((2S,5S)-5-aminotetrahydro-2H-pyran-2-yl)acetonitrile
hydrochloride (0.184 g, 1.04 mmol) [WO 2015/168246] in
dichloromethane (6.96 mL) at 0.degree. C. was treated with
triethylamine (0.436 mL, 3.13 mmol) and DMAP (2.55 mg, 0.021 mmol)
followed by 3-bromo-5-fluoro-4-methylbenzenesulfonyl chloride (0.30
g, 1.04 mmol) as a solution in dichloromethane (1.00 mL) in one
portion at 0.degree. C. and stirred at room temperature for 1 h.
The reaction mixture was poured into saturated sodium bicarbonate
solution (20 mL) and extracted with dichloromethane (2.times.20
mL). The combined organic extracts were washed with brine, dried
with sodium sulfate, filtered, and concentrated to a residue.
Purification by flash column chromatography using ethyl acetate
(contained 5% MeOH) in hexanes (0%-60%) gave the desired trans
product (185 mg, 45.3%) as a white solid. .sup.1H NMR (600 MHz,
CDCl.sub.3) .delta. 7.84 (s, 1H), 7.48 (dd, J=8.2, 1.5 Hz, 1H),
4.54 (d, J=8.0 Hz, 1H), 3.96 (ddd, J=11.1, 4.7, 2.2 Hz, 1H),
3.62-3.38 (m, 1H), 3.37-3.20 (m, 1H), 3.08 (dd, J=10.9, 10.9 Hz,
1H), 2.49 (d, J=5.9 Hz, 2H), 2.39 (d, J=2.3 Hz, 3H), 2.11-1.92 (m,
1H), 1.89-1.76 (m, 1H), 1.53-1.43 (m, 1H), 1.42-1.32 (m, 1H). LCMS
for C.sub.14H.sub.16 BrFN.sub.2O.sub.3SNa (M+Na).sup.+: m/z=413.0,
415.0; Found: 413.0, 415.0.
Step 3.
N-((3S,6R)-6-(Cyanomethyl)tetrahydro-2H-pyran-3-yl)-3-fluoro-4-met-
hyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide
##STR00687##
[1319] The desired compound was prepared according to the procedure
of example 1, step 2, using
3-bromo-N-((3S,6R)-6-(cyanomethyl)tetrahydro-2H-pyran-3-yl)-5-fluoro-4-me-
thylbenzenesulfonamide as the starting material. LCMS for
C.sub.20H.sub.28BFN.sub.2O.sub.5SNa (M+Na).sup.+: m/z=461.2; Found:
461.2.
Step 4.
3-(4-Amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-.sup.7--
yl)-N-((3S,6R)-6-(cyanomethyl)tetrahydro-2H-pyran-3-yl)-5-fluoro-4-methylb-
enzenesulfonamide
[1320] The desired compound was prepared according to the procedure
of example 1, step 3, using
7-bromo-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-amine and
N-((3S,6R)-6-(cyanomethyl)tetrahydro-2H-pyran-3-yl)-3-fluoro-4-methyl-5-(-
4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide as
the starting materials. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
9.11-8.76 (m, 2H), 8.04-7.87 (m, 2H), 7.82 (s, 1H), 7.71 (d, J=8.9
Hz, 1H), 3.81-3.66 (m, 1H), 3.50-3.36 (m, 1H), 3.17-2.90 (m, 2H),
2.70 (dd, J=16.9, 4.0 Hz, 1H), 2.57 (dd, J=16.9, 6.6 Hz, 1H), 2.23
(s, 3H), 1.83-1.54 (m, 2H), 1.51-1.16 (m, 2H). LCMS for
C.sub.20H.sub.20F.sub.4N.sub.7O.sub.3S (M+H).sup.+: m/z=514.1;
Found: 514.1.
Example 467.
3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-((3S,6R)-6-(fluoromethyl)t-
etrahydro-2H-pyran-3-yl)-4-methylbenzenesulfonamide
##STR00688##
[1321] Step 1. Tert-Butyl
((3S,6R)-6-(fluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate
##STR00689##
[1323] A solution of tert-butyl
((3S,6R)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)carbamate (0.040
g, 0.17 mmol) [J. Med. Chem. (2013), 56, 7396] in dichloromethane
(1.7 mL) at -78.degree. C. was treated with diethylaminosulfur
trifluoride (0.046 mL, 0.35 mmol) dropwise and stirred at room
temperature for 5 h. The reaction mixture was cooled back to
-78.degree. C., treated with diethylaminosulfur trifluoride (0.046
mL, 0.35 mmol), and stirred at room temperature for 14 h. The
reaction mixture was cooled to 0.degree. C., quenched with
saturated sodium bicarbonate (20 mL), and extracted with ethyl
acetate (30 mL). The organic layer was separated, washed with
brine, dried over sodium sulfate, filtered, and concentrated to a
residue. Purification by flash column chromatography using ethyl
acetate in hexanes (0%-40%) gave the desired trans product (9.3 mg,
23%) as a white solid. LCMS for C.sub.11H.sub.20FNO.sub.3Na
(M+Na).sup.+: m/z=256.1; Found: 256.1.
Step 2. (3S,6R)-6-(Fluoromethyl)tetrahydro-2H-pyran-3-amine
Hydrochloride
##STR00690##
[1325] The desired compound was prepared according to the procedure
of Example 465, step 3, using tert-butyl
((3S,6R)-6-(fluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate as the
starting material. LCMS for C.sub.6H.sub.13FNO (M+H).sup.+:
m/z=134.1; Found: 134.1.
Step 3.
3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-.sup.7-yl)-N-((3S,6R)-6-(fl-
uoromethyl)tetrahydro-2H-pyran-3-yl)-4-methylbenzenesulfonamide
[1326] The desired compound was prepared according to the procedure
of Example 424, step 8, using
(3S,6R)-6-(fluoromethyl)tetrahydro-2H-pyran-3-amine hydrochloride
as the starting material. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 8.31 (br s, 1H), 8.23 (br s, 1H), 8.05 (s, 1H), 7.93 (d,
J=1.5 Hz, 1H), 7.85-7.72 (m, 3H), 7.60 (d, J=8.1 Hz, 1H), 4.48-4.06
(m, 2H), 3.80-3.61 (m, 1H), 3.54-3.35 (m, 1H), 3.15-2.90 (m, 2H),
2.33 (s, 3H), 1.84-1.68 (m, 1H), 1.61-1.49 (m, 1H), 1.46-1.30 (m,
1H), 1.30-1.05 (m, 1H). LCMS for C.sub.18H.sub.22FN.sub.6O.sub.3S
(M+H).sup.+: m/z=421.1; Found: 421.1.
Example 468.
3-(4-Amino-2-methylimidazo[2,1-f][1,2,4]triazin-7-yl)-5-fluoro-N-(2-hydro-
xy-2-methylpropyl)-4-methylbenzenesulfonamide
##STR00691##
[1327] Step 1. Ethyl 1-amino-1H-imidazole-2-carboxylate
##STR00692##
[1329] A solution of ethyl 1H-imidazole-2-carboxylate (10.0 g, 71.4
mmol) [Combi-Blocks, SS-7811] in DMF (357 mL) was treated with
potassium tert-butoxide (74.9 mL, 74.9 mmol) dropwise and stirred
at 20.degree. C. for 1 h. The reaction mixture was then treated
with a solution of 0-(4-nitrobenzoyl)hydroxylamine (13.7 g, 74.9
mmol) in N,N-dimethylformamide (120 mL) dropwise via an addition
funnel and stirred at 20.degree. C. for 3 h. The reaction mixture
was filtered and the solid was washed with acetonitrile. The
filtrate was evaporated to give the crude product as a slightly
oily red solid that was used without further purification.
Step 2. 2-Methylimidazo[2,1-f][1,2,4]triazin-4-ol
##STR00693##
[1331] A solution of ethyl 1-amino-1H-imidazole-2-carboxylate (11.1
g, 71.4 mmol) in acetonitrile (179 mL) in a 3-neck round bottom
flask equipped with a reflux condenser was cooled to 0.degree. C.
and bubbled with HCl gas for 10 min. The reaction mixture was then
stirred at 80.degree. C. for 1 h. The reaction mixture was
concentrated and the resultant solid was triturated with diethyl
ether to give crude intermediate amidine that was used immediately
without further purification. A solution of crude intermediate
amidine in dioxane (179 mL) was treated carefully with 1.0 M sodium
bicarbonate in water (71.4 mL, 71.4 mmol) and stirred at
100.degree. C. for 1 h. The reaction mixture was concentrated and
the resultant solid was diluted with acetonitrile and filtered to
give the desired product (15.1 g) as an off-white solid that used
without further purification (it is assumed that this material
contains sodium chloride). LCMS for C.sub.6H.sub.7N.sub.4O
(M+H).sup.+: m/z=151.1; Found: 151.0.
Step 3. 7-Bromo-2-methylimidazo[2,1-f][1,2,4]triazin-4-ol
##STR00694##
[1333] A suspension of 2-methylimidazo[2,1-f][1,2,4]triazin-4-ol
(10.7 g, 71.4 mmol) in DMF (238 mL) was treated with
N-bromosuccinimide (15.3 g, 86.0 mmol) and stirred at 80.degree. C.
for 1 h. The reaction mixture was concentrated and the residue was
diluted with DCM, filtered, washed with additional DCM, and dried
to give the desired product (14.7 g) as a white solid that was used
without further purification (it is assumed that this material
contains sodium chloride from the previous step). LCMS for
C.sub.6H.sub.6BrN.sub.4O (M+H).sup.+: m/z=229.0, 231.0; Found:
229.0, 230.9.
Step 4.
7-Bromo-N-(4-methoxybenzyl)-2-methylimidazo[2,1-f][1,2,4]triazin-4-
-amine
##STR00695##
[1335] A heterogeneous mixture of
7-bromo-2-methylimidazo[2,1-f][1,2,4]triazin-4-ol (9.30 g, 40.6
mmol) and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium
hexafluorophosphate (31.1 g, 70.2 mmol) in DCE (203 mL) was treated
with 4-methoxybenzylamine (23.1 mL, 177 mmol) and DBU (4.41 mL,
29.2 mmol) and stirred at 20.degree. C. for 20.5 h. The reaction
mixture was treated with N,N-diisopropylethylamine (6.84 mL, 39.3
mmol) and stirred at 20.degree. C. for 67 h. The reaction mixture
was filtered and washed with DCM. The filtrate was concentrated to
give a crude orange oil. Purification by flash column
chromatography using ethyl acetate in hexanes (0%-30%) gave the
desired product (4.80 g, 33.9%) as a yellow solid. LCMS for
C.sub.14H.sub.15BrN.sub.5O (M+H).sup.+: m/z=348.0, 350.0; Found:
348.0, 350.0.
Step 5. 7-Bromo-2-methylimidazo[2,1-f][1,2,4 ]triazin-4-amine
##STR00696##
[1337] A solution of
7-bromo-N-(4-methoxybenzyl)-2-methylimidazo[2,1-f][1,2,4]triazin-4-amine
(8.52 g, 24.5 mmol) in TFA (12.4 mL, 161 mmol) was stirred at
80.degree. C. for 18 h. The reaction mixture was treated with
additional TFA (12.4 mL, 161 mmol) and stirred at 80.degree. C. for
5 h. The reaction mixture was concentrated and then diluted with
toluene and re-concentrated (3.times.) to give 13.7 g of a crude
green solid. The crude material was diluted with ethyl acetate (82
mL) and stirred at 80.degree. C. for 45 min. This material did not
completely dissolve. The mixture was cooled to 20.degree. C.,
diluted with hexanes (82 mL) over 5 min, and stirred overnight. The
solids were filtered and washed with hexanes to give the desired
product (8.43 g, >99%) as a green solid. LCMS for
C.sub.6H.sub.7BrN.sub.5 (M+H).sup.+: m/z=228.0, 230.0; Found:
228.0, 230.0.
Step 6.
3-Bromo-5-fluoro-N-(2-hydroxy-2-methylpropyl)-4-methylbenzenesulfo-
namide
##STR00697##
[1339] The desired compound was prepared according to the procedure
of Example 466, step 2, using 1-amino-2-methylpropan-2-ol as the
starting material. LCMS for C.sub.IIH.sub.16BrFNO.sub.3S
(M+H).sup.+: m/z=340.0, 342.0; Found: 340.0, 342.0.
Step 7.
3-Fluoro-N-(2-hydroxy-2-methylpropyl)-4-methyl-5-(4,4,5,5-tetramet-
hyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide
##STR00698##
[1341] The desired compound was prepared according to the procedure
of Example 1, step 2, using
3-bromo-5-fluoro-N-(2-hydroxy-2-methylpropyl)-4-methylbenzenesulfonamide
as the starting material. LCMS for C.sub.17H.sub.27BFNO.sub.5SNa
(M+Na).sup.+: m/z=410.2; Found: 410.1.
Step 8.
3-(4-Amino-2-methylimidazo[2,1-f][1,2,4]triazin-7-yl)-5-fluoro-N-(-
2-hydroxy-2-methylpropyl)-4-methylbenzenesulfonamide
[1342] The desired compound was prepared according to the procedure
of Example 1, step 3, using
7-bromo-2-methylimidazo[2,1-f][1,2,4]triazin-4-amine and
3-fluoro-N-(2-hydroxy-2-methylpropyl)-4-methyl-5-(4,4,5,5-tetramethyl-1,3-
,2-dioxaborolan-2-yl)benzenesulfonamide as the starting materials.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.22 (br s, 1H), 8.15
(br s, 1H), 7.83-7.71 (m, 2H), 7.71-7.58 (m, 2H), 4.41 (s, 1H),
2.69 (s, 2H), 2.28 (s, 3H), 2.21 (d, J=1.9 Hz, 3H), 1.06 (s, 6H).
LCMS for C.sub.17H.sub.22FN.sub.6O.sub.3S (M+H).sup.+: m/z=409.1;
Found: 409.3.
Example 469.
3-(4-Amino-2-(methyl-d.sub.3)imidazo[2,1-f][1,2,4]triazin-7-yl)-5-fluoro--
N-(2-hydroxy-2-methylpropyl)-4-(methyl-d.sub.3)benzenesulfonamide
##STR00699##
[1343] Step 1. I-Amino-1H-imidazole-2-carbonitrile
##STR00700##
[1345] The desired compound was prepared according to the procedure
of Example 468, step 1, using 1H-imidazole-2-carbonitrile
[PharmaBlock, PBN2011278] as the starting material.
Step 2. 2-(Methyl-d.sub.3)imidazo[2,1-f][1,2,4]triazin-4-amine
##STR00701##
[1347] The desired compound was prepared according to the procedure
of Example 468, step 2, using 1-amino-1H-imidazole-2-carbonitrile
and acetonitrile-d.sub.3 as the starting materials. LCMS for
C.sub.6H.sub.5D.sub.3N.sub.5(M+H).sup.+: m/z=153.1; Found:
153.1.
Step 3.
7-Bromo-2-(methyl-d.sub.3)imidazo[2,1-f][1,2,4]triazin-4-amine
##STR00702##
[1349] The desired compound was prepared according to the procedure
of Example 468, step 3, using
2-(methyl-d.sub.3)imidazo[2,1-f][1,2,4]triazin-4-amine as the
starting material. LCMS for C.sub.6H.sub.4D.sub.3BrN.sub.5
(M+H).sup.+: m/z=231.0, 233.0; Found: 231.1, 233.1.
Step 4.
2-(2-Fluoro-4-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
##STR00703##
[1351] A solution of 2-fluoro-1-iodo-4-nitrobenzene (1.96 g, 7.34
mmol), bis(pinacolato)diboron (1.86 g, 7.34 mmol),
dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II)
dichloromethane adduct (0.599 g, 0.734 mmol), and potassium acetate
(2.38 g, 24.2 mmol) in DMSO (14.7 mL) in a seal-able tube was
degassed with nitrogen for 15 min, sealed, and stirred at
100.degree. C. for 2.5 h. The reaction mixture was cooled to room
temperature, diluted with water and ethyl acetate, and filtered
over Celite. The aqueous layer was separated and re-extracted with
ethyl acetate. The combined organic layers were washed with brine,
dried over magnesium sulfate, filtered, and concentrated to a brown
oil. Purification by flash column chromatography using ethyl
acetate in hexanes (0%-20%) gave the desired product (1.60 g,
81.6%).
Step 5. 2-Fluoro-1-(methyl-d.sub.3)-4-nitrobenzene
##STR00704##
[1353] A solution of
2-(2-fluoro-4-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(0.920 g, 3.45 mmol) and cesium fluoride (1.83 g, 12.1 mmol) in DMF
(10.6 mL) and water (2.12 mL) in a seal-able tube was treated with
iodomethane-d.sub.3 (1.07 mL, 17.2 mmol), degassed with nitrogen
for 5 min, and treated with
bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)
(0.061 g, 0.086 mmol). The reaction mixture was degassed with
nitrogen for another 5 min, sealed, and heated at 45.degree. C. for
21 h. The reaction mixture was cooled to room temperature, diluted
with water and ethyl acetate, and filtered over Celite. Three
layers were observed during separation. The dark middle layer was
filtered again over Celite and combined with the other filtrate.
The aqueous layer was separated and re-extracted with ethyl acetate
(2.times.). The combined organic layers were washed with brine,
dried over sodium sulfate, filtered, and concentrated to an oil.
Purification by flash column chromatography using ethyl acetate in
hexanes (0%-10%) gave the desired product (303 mg, 55.6%).
Step 6. 1-Bromo-3-fluoro-2-(methyl-d.sub.3)-5-nitrobenzene
##STR00705##
[1355] A solution of 2-fluoro-1-(methyl-d.sub.3)-4-nitrobenzene
(0.303 g, 1.92 mmol) in sulfuric acid (1.72 mL) and water (0.19 mL)
was treated with silver sulfate (0.299 g, 0.958 mmol) followed by
bromine (0.099 mL, 1.92 mmol), and stirred at room temperature for
16 h. The reaction mixture was treated with additional bromine
(0.099 mL, 1.92 mmol) and stirred at room temperature for 22 h. The
reaction mixture was treated with additional silver sulfate (0.299
g, 0.958 mmol) followed by bromine (0.050 mL, 0.958 mmol) and
stirred at room temperature for 3 days. The reaction mixture was
poured into ice water, diluted with ethyl acetate, warmed to room
temp, and filtered to remove solids. The solids were washed with
water and ethyl acetate. The layers were separated and the aqueous
layer was extracted with ethyl acetate (3.times.). The combined
organic layers were washed with brine, dried over magnesium
sulfate, filtered, and concentrated to an amber oil. Purification
by flash column chromatography using ethyl acetate in hexanes
(0%-10%) gave the desired product (496 mg, 109%).
Step 7. 3-Bromo-5-fluoro-4-(methyl-d.sub.3)aniline
##STR00706##
[1357] A solution of
1-bromo-3-fluoro-2-(methyl-d.sub.3)-5-nitrobenzene (0.454 g, 1.92
mmol) in ethanol (7.98 mL) was treated with concentrated HCl (2.23
mL, 26.8 mmol) followed by tin(II) chloride (1.09 g, 5.75 mmol) and
stirred at room temperature for 15 h. The reaction mixture was
filtered to remove solids and the filtrate was quenched with 1 N
NaOH until the mixture reached pH 10. There were salts that
precipitated and this mixture was diluted with ethyl acetate and
filtered over Celite. The aqueous layer from the filtrate was
separated and re-extracted with ethyl acetate (2.times.). The
combined organic layers were washed with brine, dried over
magnesium sulfate, filtered, and concentrated to an oil.
Purification by flash column chromatography using ethyl acetate in
hexanes (0%-20%) gave the desired product (32.0 mg, 8.07%). LCMS
for C.sub.7H.sub.5D.sub.3BrFN (M+H).sup.+: m/z=207.0, 209.0; Found:
206.9, 209.0.
Step 8. 3-Bromo-5-fluoro-4-(methyl-d.sub.3)benzenesulfonyl
Chloride
##STR00707##
[1359] The desired compound was prepared according to the procedure
of Example 466, step 1, using
3-bromo-5-fluoro-4-(methyl-d.sub.3)aniline as the starting
material.
Step 9.
3-Bromo-5-fluoro-N-(2-hydroxy-2-methylpropyl)-4-(methyl-d)benzenes-
ulfonamide
##STR00708##
[1361] The desired compound was prepare according to the procedure
of Example 466, step 2, using
3-bromo-5-fluoro-4-(methyl-d.sub.3)benzenesulfonyl chloride and
1-amino-2-methylpropan-2-ol as the starting materials. LCMS for
C.sub.11H.sub.12D.sub.3BrFNO.sub.3SNa (M+Na).sup.+: m/z=365.0,
367.0; Found: 364.9, 367.0.
Step 10.
3-Fluoro-N-(2-hydroxy-2-methylpropyl)-4-(methyl-d.sub.3)-5-(4,4,5-
,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide
##STR00709##
[1363] The desired compound was prepared according to the procedure
of Example 1, step 2, using
3-bromo-5-fluoro-N-(2-hydroxy-2-methylpropyl)-4-(methyl-d.sub.3)benzenesu-
lfonamide as the starting material. LCMS for
C.sub.17H.sub.24D.sub.3BrFNO.sub.5SNa (M+Na).sup.+: m/z=413.2;
Found: 413.2.
Step 11.
3-(4-Amino-2-(methyl-d.sub.3)imidazo[2,1-f][1,2,4]triazin-7-yl)-5-
-fluoro-N-(2-hydroxy-2-methylpropyl)-4-(methyl-d.sub.3)benzenesulfonamide
[1364] The desired compound was prepared according to the procedure
of Example 1, step 3, using
3-fluoro-N-(2-hydroxy-2-methylpropyl)-4-(methyl-d.sub.3)-5-(4,4,5,5-tetra-
methyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide and
7-bromo-2-(methyl-d.sub.3)imidazo[2,1-f][1,2,4]triazin-4-amine as
the starting materials. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
8.22 (br s, 1H), 8.15 (br s, 1H), 7.80-7.71 (m, 2H), 7.65 (dd,
J=9.0, 1.7 Hz, 1H), 7.62 (s, 1H), 4.41 (s, 1H), 2.68 (s, 2H), 1.05
(s, 6H). LCMS for C.sub.17H.sub.16D.sub.6FN.sub.6O.sub.3S
(M+H).sup.+: m/z=415.2; Found: 415.1.
Example 470.
3-(4-Amino-2-(hydroxymethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-5-fluoro-N-
-(2-hydroxy-2-methylpropyl)-4-methylbenzenesulfonamide
##STR00710##
[1365] Step 1.
2-(Diethoxymethyl)imidazo[2,1-f][1,2,4]triazin-4-amine
##STR00711##
[1367] A solution of 1-amino-1H-imidazole-2-carbonitrile (0.533 g,
4.93 mmol) in ethanol (7.0 mL) in a microwave vial was treated with
a solution of methyl 2,2-diethoxyacetimidate (0.954 g, 5.92 mmol)
in ethanol (2.9 mL) over 2-3 min and stirred at room temperature
for 10 min. The reaction mixture was treated with triethylamine
(0.687 mL, 4.93 mmol) over 1 min and heated in a microwave at
120.degree. C. for 2 h. The reaction mixture was concentrated,
diluted with DCM, and concentrated again. The residue was diluted
with ethyl acetate and water. Brine was added to help with the
emulsion. The aqueous layer was separated and extracted with ethyl
acetate. The combined organic layers were washed with brine, dried
over magnesium sulfate, filtered, and concentrated to a brown oil.
Purification by flash column chromatography using methanol in
dichloromethane (0%-5%) gave the desired product (858 mg, 64.6%).
LCMS for C.sub.10H.sub.15N.sub.5O.sub.2Na (M+Na).sup.+: m/z=260.1;
Found: 260.1.
Step 2.
7-Bromo-2-(diethoxymethyl)imidazo[2,1-f][1,2,4]triazin-4-amine
##STR00712##
[1369] The desired compound was prepared according to the procedure
of Example 468, step 3, using
2-(diethoxymethyl)imidazo[2,1-f][1,2,4]triazin-4-amine as the
starting material. LCMS for C.sub.10H.sub.14BrN.sub.5O.sub.2Na
(M+Na).sup.+: m/z=338.0, 340.0; Found: 338.1, 340.1.
Step 3.
4-Amino-7-bromoimidazo[2,1-f][1,2,4]triazine-2-carbaldehyde
##STR00713##
[1371] A solution of
7-bromo-2-(diethoxymethyl)imidazo[2,1-f][1,2,4]triazin-4-amine
(0.250 g, 0.791 mmol) in tetrahydrofuran (0.47 mL) was treated with
6 N hydrochloric acid (1.11 mL) and stirred at 90.degree. C. for 1
h. The reaction mixture was concentrated to give the desired
product as a white solid that was used without further
purification. LCMS for C.sub.6H.sub.5BrN.sub.5O (M+H): m/z=242.0,
244.0; Found: 242.0, 244.0.
Step 4.
(4-Amino-7-bromoimidazo[2,1-f][1,2,4]triazin-2-yl)methanol
##STR00714##
[1373] A solution of
4-amino-7-bromoimidazo[2,1-f][1,2,4]triazine-2-carbaldehyde (0.191
g, 0.789 mmol) in methanol (0.99 mL) was treated with sodium
borohydride (0.060 g, 1.58 mmol) in portions at room temperature
and stirred for 45 min. The reaction mixture was quenched with
saturated ammonium chloride, concentrated to remove methanol, and
diluted with water and ethyl acetate. The mixture was filtered. The
aqueous layer of the filtrate was separated and extracted with
ethyl acetate. The combined organic layers were washed with brine,
then dried over magnesium sulfate, filtered, and concentrated to a
yellow solid. This solid was dissolved in methanol (4-5 mL),
stirred at 60.degree. C. for 1 h, cooled to room temperature, and
stirred for 105 min.
[1374] The solids were isolated by filtration and washed with
methanol (1 mL) to give the desired product (54.0 mg, 28.0% for 2
steps). LCMS for C.sub.6H.sub.7BrN.sub.5O (M+H).sup.+: m/z=244.0,
246.0; Found: 243.9, 245.9.
Step 5.
3-(4-Amino-2-(hydroxymethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-5-f-
luoro-N-(2-hydroxy-2-methylpropyl)-4-methylbenzenesulfonamide
[1375] The desired compound was prepared according to the procedure
of example 1, step 3, using
3-fluoro-N-(2-hydroxy-2-methylpropyl)-4-methyl-5-(4,4,5,5-tetramethyl-1,3-
,2-dioxaborolan-2-yl)benzenesulfonamide and
(4-amino-7-bromoimidazo[2,1-f][1,2,4]triazin-2-yl)methanol as the
starting materials. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
8.29 (br s, 1H), 8.22 (br s, 1H), 7.78 (s, 1H), 7.75 (s, 1H),
7.70-7.64 (m, 1H), 7.61 (s, 1H), 5.15 (t, J=6.3 Hz, 1H), 4.41 (s,
1H), 4.31 (d, J=6.3 Hz, 2H), 2.68 (s, 2H), 2.20 (d, J=2.0 Hz, 3H),
1.06 (s, 6H). LCMS for C.sub.17H.sub.22FN.sub.6O.sub.4S
(M+H).sup.+: m/z=425.1; Found: 425.1.
Example 471.
N-(3-(8-Aminoimidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)tetrahydro-2H-pyr-
an-4-sulfonamide
##STR00715##
[1376] Step 1.
N-(4-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahy-
dro-2H-pyran-4-sulfonamide
##STR00716##
[1378] The desired compound was prepared according to the procedure
of Example 466, step 2, using tetrahydro-2H-pyran-4-sulfonyl
chloride [Aurum Pharmatech, Z-2491] and
4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
[Boron Molecular, BM139] as the starting materials. LCMS for
C.sub.18H.sub.28BNO.sub.5SNa (M+Na).sup.+: m/z=404.2; Found:
404.1.
Step 2.
N-(3-(8-Aminoimidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)tetrahydro-
-2H-pyran-4-sulfonamide
[1379] The desired compound was prepared according to the procedure
of example 1, step 3, using
N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahy-
dro-2H-pyran-4-sulfonamide and 3-bromoimidazo[1,2-a]pyrazin-8-amine
as the starting materials. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 9.90 (br s, 1H), 7.60 (s, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.28
(dd, J=8.2, 2.3 Hz, 1H), 7.25-7.16 (m, 3H), 6.96 (s, 2H), 3.97-3.75
(m, 2H), 3.49-3.13 (m, 3H), 2.11 (s, 3H), 1.94-1.80 (m, 2H),
1.75-1.51 (m, 2H). LCMS for C.sub.18H.sub.22N.sub.5O.sub.3S
(M+H).sup.+: m/z=388.1; Found: 388.1.
Example 472.
(1-((3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylph-
enyl)sulfonyl)piperidin-3-yl)methanol
##STR00717##
[1380] Step 1. 5-(Trifluoromethyl)pyrazin-2-amine
##STR00718##
[1382] 2-Chloro-5-(trifluoromethyl)pyrazine (5.0 g, 27 mmol)
(Oakwood Products, 075803) was stirred in ammonium hydroxide (190
mL, 2.7 mol) and heated to 80.degree. C. for 3.5 h in a sealed
pressure vessel. After cooling to rt, the aqueous mixture was
extracted with DCM (4.times.). The extracts were combined, dried
over sodium sulfate, filtered, and concentrated to afford the title
compound as a white solid (4.0 g, 90%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.34 (s, 1H), 8.01 (s, 1H), 5.01 (br s, 2H).
LCMS for C.sub.5H.sub.5F.sub.3N.sub.3(M+H).sup.+: calculated
m/z=164.0; found 164.1.
Step 2. 3-Cloro-5-(trifluoromethyl)pyrazin-2-amine
##STR00719##
[1384] 5-(Trifluoromethyl)pyrazin-2-amine (4.56 g, 28.0 mmol) was
stirred in NMP (135 mL, 1400 mmol) and N-chlorosuccinimide (3.73 g,
28.0 mmol) was added. The reaction mixture was stirred at rt for 6
h. The reaction mixture was poured into sat. sodium thiosulfate
(100 mL) and diluted with water (500 mL). The mixture was extracted
with ethyl acetate (4.times.200 mL). The combined extracts were
washed with brine (3.times.), dried over sodium sulfate, filtered,
and concentrated. Purification via silica gel column (0-35%
EtOAc/hexanes) afforded the title compound as a white solid (2.32
g, 42.0%). LCMS for C.sub.5H.sub.4ClF.sub.3N.sub.3(M+H).sup.+:
calculated m/z=198.0; found 198.0.
Step 3. 8-Chloro-6-(trifluoromethyl)imidazo[1,2-a]pyrazine
##STR00720##
[1386] To a solution of 3-chloro-5-(trifluoromethyl)pyrazin-2-amine
(2.32 g, 11.7 mmol) in EtOH (84 mL) was slowly added
chloroacetaldehyde (37.3 mL, 294 mmol, 50% in H.sub.2O). The
reaction mixture was portioned into seven 20-mL microwave vials,
and then each was heated at 150.degree. C. for 20 min in a
microwave reactor. The reaction mixtures were combined and
concentrated, the residue was diluted with DCM, and triethylamine
was added cautiously to adjust pH.gtoreq.7. Purification via silica
gel chromatography (0-50% EtOAc/hexanes) afforded the title
compound as a brown oil (1.93 g, 74.2%). LCMS for
C.sub.7H.sub.4ClF.sub.3N.sub.3(M+H).sup.+: calculated m/z=222.0;
found 221.9.
Step 4.
3-Bromo-8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyrazine
##STR00721##
[1388] To a solution of
8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyrazine (0.37 g, 1.7
mmol) in DMF (11 mL) was added N-bromosuccinimide (0.30 g, 1.7
mmol). The reaction mixture was heated at 60.degree. C. for 2 h.
The reaction mixture was cooled to rt and poured into 40% sat.
Na.sub.2S.sub.2O.sub.3 (50 mL). The aqueous mixture was then
extracted with DCM (3.times.40 mL). The combined organic layers
were washed with brine (75 mL), dried over Na.sub.2SO.sub.4,
filtered, and concentrated. Purification via silica gel
chromatography (10-40% EtOAc/hexanes) afforded the title compound
as a white solid (0.41 g, 82%). LCMS for
C.sub.7H.sub.3BrClF.sub.3N.sub.3(M+H).sup.+: calculated m/z=299.9,
301.9; found 299.9, 301.8.
Step 5.
3-Bromo-N-(4-methoxybenzyl)-6-(trifluoromethyl)imidazo[1,2-a]pyraz-
in-8-amine
##STR00722##
[1390] A mixture of
3-bromo-8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyrazine (0.35 g,
1.2 mmol), N,N-diisopropylethylamine (0.40 mL, 2.3 mmol), and
4-methoxybenzylamine (0.17 mL, 1.3 mmol) in iPrOH (5.0 mL) was
heated at 110.degree. C. for 15 min in a microwave. The resulting
white suspension was washed with water (3.times.). The resulting
white solid was dried in vacuo overnight to afford the title
compound as a white solid (0.53 g, >99%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.71 (t, J=6.0 Hz, 1H), 7.97 (s, 1H), 7.80
(s, 1H), 7.32 (d, J=8.6 Hz, 2H), 6.85 (d, J=8.6 Hz, 2H), 4.59 (d,
J=6.0 Hz, 2H), 3.70 (s, 3H). .sup.19F NMR (376 MHz, DMSO-d.sub.6)
.delta. -66.99. LCMS for C.sub.15H.sub.13BrF.sub.3N.sub.4O
(M+H).sup.+: calculated m/z=401.0, 403.0; found 401.0, 403.0.
Step 6.
3-Bromo-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-8-amine
##STR00723##
[1392] A solution of
3-bromo-N-(4-methoxybenzyl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-8-am-
ine (0.53 g, 1.2 mmol) in TFA (2.9 mL) was heated at 55.degree. C.
for 1 h. The reaction mixture was concentrated and then diluted
with water (3.0 mL). With the reaction vial in a 0.degree. C. bath,
the aqueous mixture was basified with 1.0 M NaOH (7.5 mL). The bath
was removed, and the aqueous mixture was stirred for 5 min. The
resulting white precipitate was collected via filtration, washed
with water (2.times.10 mL) and dried to afford the crude product as
a white solid (0.440 g). Purification via silica gel chromatography
(5-40% EtOAc/DCM) afforded the title compound as a white solid
(0.25 g, 77%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.98 (s,
1H), 7.81 (s, 1H), 7.73 (br s, 2H). .sup.19F NMR (376 MHz,
DMSO-d.sub.6) .delta. -66.77. LCMS for
C.sub.7H.sub.5BrF.sub.3N.sub.4(M+H).sup.+: calculated m/z=281.0,
283.0; found 280.9, 282.9.
Step 7.
3-(o-Tolyl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-8-amine
##STR00724##
[1394] A mixture of
dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)
dichloromethane adduct (0.52 g, 0.64 mmol), o-tolylboronic acid
(1.4 g, 10 mmol), and
3-bromo-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-8-amine (1.0 g, 3.
6 mmol) in THF (36 mL) and 1.0 M potassium carbonate in water (18
mL, 18 mmol) was degassed with N.sub.2 for 5 min and then heated at
80.degree. C. for 5 h. The reaction mixture was filtered through
Celite, rinsing with EtOAc and water. The resulting mixture was
washed with water (2.times.75 mL) and brine (70 mL). The organic
layer was then dried over sodium sulfate, filtered, and
concentrated. Purification via silica gel chromatography (1-88%
EtOAc/hexanes) afforded the title compound as a white solid (1.1 g,
>99% yield). LCMS for C.sub.14H.sub.12F.sub.3N.sub.4
(M+H).sup.+: calculated m/z=293.1; found 293.1.
Step 8.
3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methyl-
benzenesulfonyl Chloride
##STR00725##
[1396] A 45-mL scintillation vial was charged with
3-(o-tolyl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-8-amine (0.49
g, 1.7 mmol). The vial was placed under nitrogen, and
dichloromethane (20 mL) was added. The reaction vial was placed in
an ice bath, and chlorosufluric acid (1.1 mL, 17 mmol) added over 2
min. After 5 min, the ice bath was removed; the mixture was warmed
to rt and then heated at 50.degree. C. for 3 h. The reaction
mixture was again cooled to 0.degree. C., and an additional portion
of chlorosufluric acid (1.1 ml, 17 mmol) was added over 1 min. The
mixture was warmed to rt and then heated at 50.degree. C. for 3.5
h. The reaction mixture was cooled to rt and diluted with DCM (20
mL). The mixture added slowly to a stirred mixture of ice water
(100 mL) and DCM (80 mL). The organic layer was removed, and the
aqueous layer was extracted with DCM (2.times.100 mL). The combined
organic layers were dried over MgSO.sub.4, filtered, and
concentrated to afford the title compound as an orange-brown solid
(0.53 g, 82%). LCMS for C.sub.14H.sub.11ClF.sub.3N.sub.4O.sub.2S
(M+H).sup.+: calculated m/z=391.0; found 391.0.
Step 9.
(1-((3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-m-
ethylphenyl)sulfonyl)piperidin-3-yl)methanol
[1397] To a mixture of piperidin-3-ylmethanol (3.0 .mu.L, 0.027
mmol), triethylamine (11 .mu.L, 0.080 mmol), and DMAP (0.3 mg, 3
.mu.mol) in DMA (0.24 mL) at 0.degree. C. was added
3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylbenzene-
sulfonyl chloride (10 mg, 0.027 mmol) in a single portion. The
reaction mixture was allowed to come to rt and stirred for 2 h. The
reaction mixture was again cooled to 0.degree. C., and the reaction
was quenched with MeOH. Purification via preparative HPLC on a C-18
column (pH 10, 32-52% MeCN/0.1% NH.sub.4OH (aq) over 5 min, 60
mL/min) afforded the desired product as a white solid (7.0 mg,
56%). .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. 7.84 (s, 1H),
7.78 (dd, J=8.2, 1.9 Hz, 1H), 7.74-7.70 (m, 3H), 7.67 (br s, 2H),
4.55 (t, J=5.3 Hz, 1H), 3.66 (dd, J=11.4, 3.7 Hz, 1H), 3.53 (d,
J=10.9 Hz, 1H), 3.37-3.25 (m, 1H), 3.23-3.09 (m, 1H), 2.37-2.30 (m,
1H), 2.30 (s, 3H), 2.08 (t, J=10.8 Hz, 1H), 1.73-1.61 (m, 2H),
1.62-1.56 (m, 1H), 1.55-1.42 (m, 1H), 1.01-0.83 (m, 1H). .sup.19F
NMR (376 MHz, DMSO-d.sub.6) .delta. -66.70. LCMS for
C.sub.20H.sub.23F.sub.3N.sub.5O.sub.3S (M+H).sup.+: calculated
m/z=470.1; found 470.2.
Example 473.
3-(2-Methyl-5-(methylsulfonyl)phenyl)-6-(3-methylpyridin-4-yl)imidazo[1,2-
-a]pyrazin-8-amine Trifluoroacetate
##STR00726##
[1398] Step 1.
6-Bromo-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-8-amin-
e
##STR00727##
[1400] A mixture of 6-bromo-3-iodoimidazo[1,2-a]pyrazin-8-amine
(680 mg, 2.0 mmol), bis(pinacolato)diboron (490 mg, 1.7 mmol), and
tetrakis(triphenylphosphine)palladium(0) (120 mg, 0.10 mmol) in
ethanol (10 mL) and 2.0 M Na.sub.2CO.sub.3 in water (1.7 mL, 3.3
mmol) was degassed for 5 min with N.sub.2. The reaction mixture was
then heated in a microwave reactor at 130.degree. C. for 20 min.
The precipitated solid was collected via filtration, washed with
MeOH, and air dried to yield the title compound (620 mg, 74%).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.96 (dd, J=8.0, 2.0
Hz, 1H), 7.90 (d, J=1.9 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.69 (s,
1H), 7.59 (s, 2H), 7.40 (s, 1H), 3.26 (s, 3H), 2.25 (s, 3H). LCMS
for C.sub.14H.sub.14BrN.sub.4O.sub.2S (M+H).sup.+: calculated
m/z=381.0, 383.0; found 381.0, 383.0.
Step 2.
3-(2-Methyl-5-(methylsulfonyl)phenyl)-6-(3-methylpyridin-4-yl)imid-
azo[1,2-a]pyrazin-8-amine Trifluoroacetate
[1401] A 1-dram vial was charged with
6-bromo-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-8-amin-
e (8 mg, 0.02 mmol),
dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)
dichloromethane adduct (3 mg, 4 .mu.mol), and
(3-methylpyridin-4-yl)boronic acid (11 mg, 0.084 mmol). THF (0.42
mL) and then 1.0 M potassium carbonate (53 .mu.L, 0.052 mmol) were
added. The reaction mixture was degassed with N.sub.2 briefly and
then heated at 80.degree. C. for 16 h. The reaction mixture was
diluted with MeOH and filtered through a plug of Na.sub.2SO.sub.4
and Celite. Purification via preparative HPLC on a C-18 column (pH
2, 11-31% MeCN/0.1% TFA (aq) over 5 min, 60 mL/min) afforded the
title compound as a yellow semi-solid (3.7 mg, 34%). .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 8.72 (s, 1H), 8.67 (d, J=5.7 Hz,
1H), 8.00-7.94 (m, 2H), 7.89-7.82 (m, 2H), 7.72 (d, J=8.8 Hz, 1H),
7.70 (s, 1H), 7.60 (br s, 2H), 3.25 (s, 3H), 2.52 (s, 3H), 2.33 (s,
3H). LCMS for C.sub.20H.sub.20N.sub.5O.sub.2S (M+H).sup.+:
calculated m/z=394.1; found 394.1.
[1402] Examples 474 to 486 were synthesized according to procedures
analogous to the synthesis of Example 473, and the data are listed
in Table 20.
TABLE-US-00024 TABLE 20 ##STR00728## LCMS Ex. Name R.sup.8 [M +
H].sup.+ No. .sup.1H NMR Spectra 474
2-(3-(8-Amino-3-(2-methyl-5-(methylsulfonyl)
phenyl)imidazo[1,2-a]pyrazin-6-yl)phenyl) acetonitrile
trifluoroacetate ##STR00729## 418.1 475
6-(4-(Difluoromethyl)phenyl)-3-(2-methyl-5-
(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-8- amine
trifluoroacetate ##STR00730## 429.1 476
6-(3-Fluoropyridin-4-yl)-3-(2-methyl-5-
(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-8- amine
trifluoroacetate ##STR00731## 398.1 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.60 (d, J = 3.3 Hz, 1H), 8.52 (dd, J = 5.0,
1.0 Hz, 1H), 8.06 (dd, J = 7.0, 5.0 Hz, 1H), 7.99 (d, J = 6.9 Hz,
2H), 7.84 (d, J = 1.0 Hz, 2H), 7.76 (d, J = 9.3 Hz, 1H), 7.52 (s,
2H), 3.26 (s, 3H), 2.32 (s, 3H). 477
6-(2-Methoxypyridin-3-yl)-3-(2-methyl-5-
(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-8- amine
trifluoroacetate ##STR00732## 410.0 478
6-(2-Fluoro-6-methoxyphenyl)-3-(2-methyl-5-
(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-8- amine
trifluoroacetate ##STR00733## 427.2 479
6-(1-Methyl-1H-pyrazol-5-yl)-3-(2-methyl-5-
(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-8- amine
trifluoroacetate ##STR00734## 383.1 480 4-(8-Amino-3-(2-methyl-5-
(methylsulfonyl)phenyl) imidazo[1,2-a]pyrazin-6-yl)-3-fluoro-N,N-
dimethylbenzamide ##STR00735## 468.1 481 (3-(8-Amino-3-(2-methyl-5-
(methylsulfonyl)phenyl) imidazo[1,2-a]pyrazin-6-yl)-2-
fluorophenyl)methanol ##STR00736## 427.1 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.98 (dd, J = 8.1, 2.0 Hz, 1H), 7.95 (d, J =
1.9 Hz, 1H), 7.92 (td, J = 7.8, 1.9 Hz, 1H), 7.79-7.72 (m, 2H),
7.59 (s, 1H), 7.47-7.40 (m, 1H), 7.30- 7.22 (m, 3H), 5.25 (t, J =
5.5 Hz, 1H), 4.55 (d, J = 5.5 Hz, 2H), 3.26 (s, 3H), 2.29 (s, 3H).
482 6-(6-Aminopyridin-3-yl)-3-(2-methyl-5-
(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-8- amine
trifluoroacetate ##STR00737## 395.1 483
6-(3-Fluoro-2-methoxypyridin-4-yl)-3-(2-methyl-
5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin- 8-amine
trifluoroacetate ##STR00738## 428.1 484
6-(3-Chloropyridin-4-yl)-3-(2-methyl-5-
(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-8- amine
trifluoroacetate ##STR00739## 414.0 485
6-(3-Methoxypyridin-4-yl)-3-(2-methyl-5-
(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-8- amine
trifluoroacetate ##STR00740## 410.1 486
2-(3-(8-Amino-3-(2-methyl-5-(methylsulfonyl)
phenyl)imidazo[1,2-a]pyrazin-6-yl)phenoxy) acetonitrile
trifluoroacetate ##STR00741## 434.2
Example 487.
6-(2-Fluoro-4-(pyrrolidin-1-ylmethyl)phenyl)-3-(2-methyl-5-(methylsulfony-
l)phenyl)imidazo[1,2-a]pyrazin-8-amine
##STR00742##
[1403] Step 1.
4-(8-Amino-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-6-y-
l)-3-fluorobenzaldehyde
##STR00743##
[1405] The title compound was synthesized according to experimental
procedure analogous to the synthesis of Example 473, Step 1,
substituting (2-fluoro-4-formylphenyl)boronic acid for
(3-methylpyridin-4-yl)boronic acid. Purification via silica gel
chromatography (12-100% EtOAc in DCM) afforded a yellow-orange
solid (16 mg), which contained the title compound as a 3:2 mixture
with an aldehyde byproduct. This material was carried forward
without further purification. LCMS for
C.sub.21H.sub.18FN.sub.4O.sub.3S (M+H).sup.+: calculated m/z=425.1;
found 425.0.
Step 2.
6-(2-Fluoro-4-(pyrrolidin-1-ylmethyl)phenyl)-3-(2-methyl-5-(methyl-
sulfonyl)phenyl)imidazo[1,2-a]pyrazin-8-amine
[1406] To a mixture of
4-(8-amino-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-6-y-
l)-3-fluorobenzaldehyde (15 mg, 0.025 mmol, 70% purity) and
pyrrolidine (6 .mu.L, 0.07 mmol) in MeOH (0.5 mL) and acetic acid
(0.7 .mu.L) was added sodium cyanoborohydride (6 mg, 0.1 mmol). The
reaction mixture was stirred overnight. The reaction was quenched
with water. Purification via prep LCMS via preparative HPLC on a
C-18 column (pH 10, MeCN/0.1% NH.sub.4OH (aq)) afforded the desired
product title compound as white solid (2.5 mg, 21%). LCMS for
C.sub.25H.sub.27FN.sub.5O.sub.2S (M+H).sup.+: calculated m/z=480.2;
found 480.2.
Example 488.
1-(4-(8-Amino-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin--
6-yl)-3-fluorophenyl)ethan-1-ol
##STR00744##
[1407] Step 1. 1-(4-Bromo-3-fluorophenyl)ethan-1-ol
##STR00745##
[1409] To a solution of 4-bromo-3-fluorobenzaldehyde (0.50 g, 2.5
mmol) in THF (10 mL) at -44.degree. C. was added methylmagnesium
bromide (0.99 mL, 3.0 mmol. 3.0 M in Et.sub.2O). The reaction
mixture was allowed to warm to rt, stirring for 3 h. The reaction
was quenched with sat. NH.sub.4Cl. The resulting aq. suspension was
extracted with EtOAc (3.times.). The combined organic layers were
dried over MgSO.sub.4, filtered, and concentrated. Purification via
silica gel chromatography (25-69% EtOAc/hexanes) afforded the
desired product as a clear liquid (0.51 g, 95%). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.50 (apparent t, J=8.0 Hz, 1H), 7.16 (d,
J=9.5 Hz, 1H), 7.02 (d, J=8.4 Hz, 1H), 4.87 (q, J=6.5 Hz, 1H), 1.47
(d, J=6.4 Hz, 3H). .sup.19F NMR (376 MHz, CDCl.sub.3) .delta.
-107.10.
Step 2.
1-(3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-
ethan-1-ol
##STR00746##
[1411] A mixture of 1-(4-bromo-3-fluorophenyl)ethan-1-ol (0.13 g,
0.59 mmol), bis(pinacolato)diboron (0.17 g, 0.65 mmol), potassium
acetate (0.17 g, 1.8 mmol), and
bis(triphenylphosphine)palladium(II) chloride (15 mg, 0.022 mmol)
in THF (4.6 mL) was degassed with N.sub.2 for 5 min. The mixture
was then heated at 140.degree. C. in a microwave for 20 min. The
reaction mixture was diluted with EtOAc and filtered through
Celite, rinsing with EtOAc. The filtrate was washed with water and
then brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated. Purification via silica gel chromatography (1-10%
MeOH in DCM) afforded a grey-brown solid (0.19 g). This material
was a mixture of the title compound and another fluorinated
impurity; it was carried on without further purification. LCMS for
C.sub.14H.sub.19BFO.sub.2 (M-OH).sup.+: calculated m/z=249.2; found
249.2.
Step 3.
1-(4-(8-Amino-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]p-
yrazin-6-yl)-3-fluorophenyl)ethan-1-ol
[1412] The title compound was synthesized according to experimental
procedure analogous to the synthesis of Example 473, Step 1,
substituting
1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethan-1-
-ol for (3-methylpyridin-4-yl)boronic acid. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.02 (d, J=8.2 Hz, 1H), 8.00-7.98 (m, 1H),
7.98-7.95 (m, 1H), 7.77-7.72 (m, 2H), 7.62 (s, 1H), 7.25 (dd,
J=8.5, 1.6 Hz, 1H), 7.23 (br s, 2H), 7.17 (dd, J=13.2, 1.6 Hz, 1H),
5.29 (d, J=4.4 Hz, 1H), 4.85-4.64 (m, 1H), 3.26 (s, 3H), 2.31 (s,
3H), 1.32 (d, J=6.5 Hz, 3H). LCMS for
C.sub.22H.sub.22FN.sub.4O.sub.3S (M+H).sup.+: calculated m/z=441.1;
found 441.1.
Example 489.
6-(5-Fluoro-2-methylpyridin-4-yl)-3-(2-methyl-5-(methylsulfonyl)phenyl)im-
idazo[1,2-a]pyrazin-8-amine Trifluoroacetate
##STR00747##
[1414] A mixture of 4-bromo-5-fluoro-2-methylpyridine (16 .mu.L),
bis(pinacolato)diboron (40 mg, 0.16 mmol), KOAc (39 mg, 0.395
mmol), and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium
(II) dichloromethane adduct (4 mg, 5 .mu.mol) in THF (0.37 mL) was
degassed with N.sub.2 for 3 min. The mixture was then heated at
140.degree. C. in a microwave for 20 min. The reaction mixture was
diluted with EtOAc and filtered through Celite, rinsing with EtOAc.
The filtrate was washed with water and then brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated to afford the crude
boronate ester.
[1415] A 1-dram vial was charged with
dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II)
dichloromethane adduct (3 mg, 4 .mu.mol) and
6-bromo-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-8-amin-
e (8 mg, 0.02 mmol). A solution containing a half portion of the
crude boronate ester in THF (0.50 mL) and then 1.0 M potassium
carbonate (53 .mu.L, 0.052 mmol) were added. The reaction mixture
was degassed with N.sub.2 for 5 min and then heated at 80.degree.
C. for 3 h. The reaction mixture was partitioned between EtOAc and
water. The organic layer was removed, and the aqueous extracted
with EtOAc (2.times.). The combined organic layers were dried over
Na.sub.2SO.sub.4 and filtered. Purification via preparative HPLC on
a C-18 column (pH 2, 14-34% MeCN/0.1% TFA (aq) over 5 min, 60
mL/min) afforded the title compound as a yellow solid (6 mg, 60%).
LCMS for C.sub.20H.sub.19FN.sub.5O.sub.2S (M+H).sup.+: calculated
m/z=412.1; found 412.0.
Example 490.
(5-(8-Amino-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-6--
yl)-6-methoxypyridin-2-yl)methanol Trifluoroacetate
##STR00748##
[1416] Step 1. (5-Bromo-6-methoxypyridin-2-yl)methanol
##STR00749##
[1418] To a suspension of methyl 5-bromo-6-methoxypicolinate (20
mg, 0.079 mmol) (Ark Pharm, AK100459) in ethanol (0.25 mL) was
added sodium borohydride (9.6 mg, 0.25 mmol). The reaction mixture
was then heated at 50.degree. C. for 2.5 h. An additional portion
of sodium borohydride (10 mg, 0.27 mmol) was added, and the
reaction mixture was heated at 50.degree. C. for an additional 2 h.
The reaction was quenched with water, and the reaction mixture was
partitioned between sat. NaHCO.sub.3 and EtOAc. The organic layer
was removed, and the aqueous mixture was extracted with EtOAc
(2.times.). The combined organic layers were washed with brine,
dried over Na.sub.2SO.sub.4, filtered, and concentrated.
Purification via silica gel chromatography (15-55% EtOAc/hexanes)
afforded the desired product as a white solid (11 mg, 64%). LCMS
for C.sub.7H.sub.9BrNO.sub.2 (M+H).sup.+: calculated m/z=218.0,
220.0; found 217.9, 220.1.
Step 2.
(5-(8-Amino-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyr-
azin-6-yl)-6-methoxypyridin-2-yl)methanol Trifluoroacetate
[1419] The title compound was synthesized according to an
experimental procedure analogous to the synthesis of Example 489,
substituting (5-bromo-6-methoxypyridin-2-yl)methanol for
4-bromo-5-fluoro-2-methylpyridine. LCMS for
C.sub.21H.sub.22N.sub.5O.sub.4S (M+H).sup.+: calculated m/z=440.1;
found 440.1.
Example 491.
6-(4-Methoxy-1H-pyrazol-5-yl)-3-(2-methyl-5-(methylsulfonyl)phenyl)imidaz-
o[1,2-a]pyrazin-8-amine Trifluoroacetate
##STR00750##
[1420] Step 1. 3-Bromo-4-methoxy-1H-pyrazole
##STR00751##
[1422] To a solution of 4-methoxy-1H-pyrazole (71 mg, 0.70 mmol)
(Synthonix, M20056) in DMF (4.7 mL) was added N-bromosuccinimide
(130 mg, 0.70 mmol). After stirring at rt for 2 h, the reaction
mixture was diluted with DCM and poured into sat.
Na.sub.2S.sub.2O.sub.3. The organic layer was removed, and the
aqueous layer was extracted twice more with DCM. The combined
organic layers were washed with brine, dried over Na.sub.2SO.sub.4,
filtered, and concentrated. Purification via silica gel
chromatography (10-80% EtOAc/hexanes) afforded the title compound
as a white solid (77 mg, 62%). LCMS for C.sub.4H.sub.6BrN.sub.2O
(M+H).sup.+: calculated m/z=177.0, 179.0; found 177.0, 178.9.
Step 2.
3-Bromo-4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole
and
5-Bromo-4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole
##STR00752##
[1424] A solution of 3-bromo-4-methoxy-1H-pyrazole (77 mg, 0.44
mmol) in THF (5.4 mL) at 0.degree. C. was treated with 2.0 M NaOtBu
in THF (0.28 mL, 0.57 mmol). Upon stirring at 0.degree. C. for 30
min, the reaction mixture was treated with
(2-(chloromethoxy)ethyl)trimethylsilane (92 .mu.L, 0.52 mmol) and
was then stirred for 2 h during which the reaction mixture came to
rt. The reaction was quenched with sat. NH.sub.4Cl and diluted with
water. The aqueous mixture was extracted with EtOAc (3.times.). The
combined organic layers were dried over Na.sub.2SO.sub.4, filtered,
and concentrated. Purification via silica gel chromatography
(10-30% EtOAc in hexanes) afforded the title compounds as 1.3:1
mixture of regioisomers (130 mg, 95%, clear oil). .sup.1H NMR (400
MHz, CDCl.sub.3) Major isomer: .delta. 7.16 (s, 1H), 5.29 (s, 2H),
3.81 (s, 3H), 3.62-3.49 (m, 2H), 0.99-0.81 (m, 2H), -0.01 (s, 9H).
Minor isomer: .delta. 7.38 (s, 1H), 5.42 (s, 2H), 3.85 (s, 3H),
3.62-3.49 (m, 2H), 0.99-0.81 (m, 2H), -0.02 (s, 9H). LCMS for
C.sub.10H.sub.20BrN.sub.2O.sub.2Si (M+H).sup.+: calculated
m/z=307.0, 309.0; found 306.9, 309.0.
Step 3.
6-(4-Methoxy-1H-pyrazol-5-yl)-3-(2-methyl-5-(methylsulfonyl)phenyl-
)imidazo[,2-a]pyrazin-8-amine Trifluoroacetate
[1425] A mixture of
3-bromo-4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole
and
5-bromo-4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole
(31 mg, 0.10 mmol, mixture of two regioisomers),
bis(pinacolato)diboron (32 mg, 0.13 mmol), potassium acetate (32
mg, 0.33 mmol), and
dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II)
dichloromethane adduct (3 mg, 4 .mu.mol) in THF (0.30 mL) was
degassed with N.sub.2 for 3 min. The mixture was then heated at
140.degree. C. in a microwave for 20 min and then again for 60 min.
Additional portions of bis(pinacolato)diboron (32 mg, 0.13 mmol)
and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II)
dichloromethane adduct (3 mg, 4 .mu.mol) were added. The reaction
mixture was degassed briefly and then heated at 140.degree. C. in a
microwave for 20 min. The reaction mixture was diluted with EtOAc
and filtered through Celite, rinsing with EtOAc. The filtrate was
washed with water and then brine, dried over Na.sub.2SO.sub.4,
filtered, and concentrated to afford the crude boronate ester.
[1426] A 1-dram vial was charged with
6-bromo-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-8-amin-
e (8 mg, 0.02 mmol) and
dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II)
dichloromethane adduct (3 mg, 4 .mu.mol). A solution of the crude
boronate ester in THF (0.50 mL) and then 1.0 M potassium carbonate
(53 .mu.L, 0.052 mmol) were added. The reaction mixture was
degassed with N.sub.2 for 5 min and then heated at 80.degree. C.
for 16 h. The reaction mixture was partitioned between EtOAc and
water. The organic layer was removed, and the aqueous layer was
extracted with EtOAc (2.times.). The combined organic layers were
washed with brine, filtered through a plug of Na.sub.2SO.sub.4, and
concentrated.
[1427] The resulting residue was dissolved in 1:1
DCM/trifluoroacetic acid (0.80 mL) and heated at 40.degree. C. for
1 h. After cooling to rt, the reaction mixture was diluted with
MeOH. Purification via preparative HPLC on a C-18 column (pH 2,
19-35% MeCN/0.1% TFA (aq) over 5 min, 60 mL/min) afforded the title
compound as a white solid (2 mg, 10%). .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.13-8.05 (m, 2H), 7.93 (s, 1H), 7.83 (s, 1H),
7.79 (d, J=8.6 Hz, 1H), 7.55 (s, 1H), 3.81 (s, 3H), 3.20 (s, 3H),
2.42 (s, 3H). LCMS for C.sub.18H.sub.19N.sub.6O.sub.3S (M+H).sup.+:
calculated m/z=399.1; found 399.1.
Example 492.
7-(2-Methyl-5-(((tetrahydro-2H-pyran-4-yl)methyl)sulfonyl)phenyl)imidazo[-
2,1-f][1,2,4]triazin-4-amine Trifluoroacetate
##STR00753##
[1428] Step 1. Sodium 3-bromo-4-methylbenzenesulfinate
##STR00754##
[1430] To a mixture of sodium sulfite (0.94 g, 7.4 mmol) and sodium
bicarbonate (0.62 g, 7.4 mmol) in water (3.1 mL) at 85.degree. C.
was added 3-bromo-4-methylbenzenesulfonyl chloride (0.50 g, 1.9
mmol). Sodium bicarbonate (0.623 g, 7.42 mmol) and then a second
portion of 3-bromo-4-methylbenzenesulfonyl chloride (0.52 g, 1.9
mmol) was added to the reaction mixture. [Note: Evolution of
CO.sub.2 was observed.] The reaction mixture was stirred at
85.degree. C. for 0.5 h before it was concentrated. The resulting
solid was triturated with EtOH (4.times., 50 mL total). The
filtrate was concentrated to afford a white solid (0.99 g,
>99%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.57 (d,
J=1.7 Hz, 1H), 7.34-7.23 (m, 2H), 2.32 (s, 3H). LCMS for
C.sub.7H.sub.8BrO.sub.2S (M+2H).sup.+: calculated m/z=234.9, 236.9;
found 235.0, 237.0.
Step 2.
4-(((3-Bromo-4-methylphenyl)sulfonyl)methyl)tetrahydro-2H-pyran
##STR00755##
[1432] To a solution of sodium 3-bromo-4-methylbenzenesulfinate (50
mg, 0.19 mmol) in DMF (1 mL) was added
4-(bromomethyl)tetrahydro-2H-pyran (26 .mu.L). The reaction mixture
was stirred at 50.degree. C. overnight. An additional portion of
4-(bromomethyl)tetrahydro-2H-pyran (26 .mu.L) was added, and the
reaction mixture was stirred at 50.degree. C. for 1 d. The reaction
mixture was diluted with water, and the aqueous mixture was
extracted with EtOAc (3.times.). The combined organic layers were
washed with brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated. Purification via silica gel chromatography (20-80%
EtOAc/hexanes) afforded the title compound as a white solid (32 mg,
49%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.07 (d, J=2.0 Hz,
1H), 7.73 (dd, J=8.0, 1.9 Hz, 1H), 7.43 (d, J=7.9 Hz, 1H), 3.93
(dd, J=12, 2.4 Hz, 2H), 3.41 (td, J=11.7, 1.9 Hz, 2H), 3.01 (d,
J=6.4 Hz, 2H), 2.49 (s, 3H), 2.37-2.19 (m, 1H), 1.87-1.75 (m, 2H),
1.53-1.35 (m, 2H). LCMS for C.sub.13H.sub.18BrO.sub.3S (M+H).sup.+:
calculated m/z=333.0, 335.0; found 333.0, 335.0.
Step 3.
4,4,5,5-Tetramethyl-2-(2-methyl-5-(((tetrahydro-2H-pyran-4-yl)meth-
yl)sulfonyl)phenyl)-1,3,2-dioxaborolane
##STR00756##
[1434] A mixture of
4-(((3-bromo-4-methylphenyl)sulfonyl)methyl)tetrahydro-2H-pyran (32
mg, 0.096 mmol), bis(pinacolato)diboron (32 mg, 0.13 mmol),
potassium acetate (32 mg, 0.33 mmol), and
dichlorobis(triphenylphosphine)palladium(II) (3 mg, 4 .mu.mol) in
THF (0.3 mL) was degassed briefly with N.sub.2. The mixture was
heated in a microwave at 140.degree. C. for 20 min. The reaction
mixture was diluted with EtOAc and filtered through Celite, rinsing
with EtOAc. The filtrate was washed with water and then brine,
dried over Na.sub.2SO.sub.4, filtered, and concentrated to afford
the title compound as a crude product, which was utilized without
further purification. LCMS for C.sub.19H.sub.30BO.sub.5S
(M+H).sup.+: calculated m/z=381.2; found 381.2.
Step 4.
7-(2-Methyl-5-(((tetrahydro-2H-pyran-4-yl)methyl)sulfonyl)phenyl)i-
midazo[2,1-f][1,2,4]triazin-4-amine Trifluoroacetate
[1435] A 1-dram vial was charged with
7-bromoimidazo[2,1-f][1,2,4]triazin-4-amine (17 mg, 0.079 mmol),
4,4,5,5-tetramethyl-2-(2-methyl-5-(((tetrahydro-2H-pyran-4-yl)methyl)sulf-
onyl)phenyl)-1,3,2-dioxaborolane (crude product from Step 3), and
dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II)
dichloromethane adduct (13 mg, 0.016 mmol). THF (1.3 mL) and then
1.0 M potassium carbonate (160 .mu.L, 0.16 mmol) were then added.
The reaction mixture was degassed with N.sub.2 for 5 min and then
heated at 80.degree. C. overnight. The reaction mixture was diluted
with MeOH and filtered through a plug of Na.sub.2SO.sub.4 and
Celite. Purification via preparative HPLC on a C-18 column (pH 2,
17-37% MeCN/0.1% TFA (aq) over 5 min, 60 mL/min) afforded the title
compound as a white solid (23 mg, 58%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.39 (br s, 1H), 8.29 (br s, 1H), 8.09 (s,
1H), 8.01 (d, J=2.0 Hz, 1H), 7.89 (dd, J=8.1, 2.0 Hz, 1H), 7.83 (s,
1H), 7.68 (d, J=8.1 Hz, 1H), 3.82-3.70 (m, 2H), 3.32 (d, J=6.4 Hz,
2H), 3.27 (td, J=11.7, 2.1 Hz, 2H), 2.36 (s, 3H), 2.04 (ttd,
J=10.7, 6.3, 3.1 Hz, 1H), 1.68 (dd, J=12.9, 1.9 Hz, 2H), 1.32 (dtd,
J=13.2, 11.4, 4.3 Hz, 2H). LCMS for C.sub.18H.sub.22N.sub.5O.sub.3S
(M+H).sup.+: calculated m/z=388.1; found 388.0.
Example 493.
7-(2-Methyl-5-((3,3,3-trifluoropropyl)sulfonyl)phenyl)imidazo[2,1-f][1,2,-
4]triazin-4-amine Trifluoroacetate
##STR00757##
[1437] The title compound was synthesized according to experimental
procedures analogous to the synthesis of Example 492, substituting
1,1,1-trifluoro-3-iodopropane for
4-(bromomethyl)tetrahydro-2H-pyran in step 2. LCMS for
C.sub.15H.sub.15F.sub.3N.sub.5O.sub.2S (M+H).sup.+: calculated
m/z=386.1; found 386.0.
Example 494.
4-((3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphe-
nyl)sulfonyl)butan-2-ol
##STR00758##
[1438] Step 1. 4-((3-Bromo-4-methylphenyl)sulfonyl)butan-2-one
##STR00759##
[1440] A mixture of sodium 3-bromo-4-methylbenzenesulfinate (0.20
g, 0.78 mmol) and but-3-en-2-one (70 .mu.L, 0.86 mmol) in AcOH
(0.18 mL) and water (1.8 mL) was heated overnight at 110.degree. C.
After cooling to rt, the reaction mixture was diluted with water.
The aqueous mixture was extracted with EtOAc (3.times.). The
combined organic layers were washed with brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated to afford the title
compound as a white solid (0.19 g, 80%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.05 (d, J=1.9 Hz, 1H), 7.73 (dd, J=8.0, 1.9
Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 3.41-3.32 (m, 2H), 2.97-2.88 (m,
2H), 2.49 (s, 3H), 2.19 (s, 3H). LCMS for C11H.sub.14BrO.sub.3S
(M+H).sup.+: calculated m/z=305.0, 307.0; found 304.9, 306.9.
Step 2. 4-((3-Bromo-4-methylphenyl)sulfonyl)butan-2-ol
##STR00760##
[1442] Sodium borohydride (2.78 mg, 0.073 mmol) was added to a
solution of 4-((3-bromo-4-methylphenyl)sulfonyl)butan-2-one (16 mg,
0.052 mmol) in 1:1 MeOH/THF (1.4 mL) at 0.degree. C. The reaction
mixture was stirred for 1.5 h at 0.degree. C. The reaction was
quenched with water (0.3 mL). The reaction mixture was warmed to
rt, and sat. NaHCO.sub.3 was added. The aqueous mixture was
extracted with EtOAc (3.times.). The combined organic layers were
washed with brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated. Purification via silica gel chromatography (10-40%
EtOAc in DCM) afforded the title compound as a white residue (15
mg, 93%). LCMS for C.sub.11H.sub.16BrO.sub.3S (M+H).sup.+:
calculated m/z=307.0, 309.0; found 307.0, 309.0.
Step 3.
4-((4-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl-
)sulfonyl)butan-2-ol
##STR00761##
[1444] The title compound was synthesized according to an
experimental procedure analogous to the synthesis of Example 492,
Step 3, substituting 4-((3-bromo-4-methylphenyl)sulfonyl)butan-2-ol
for
4-(((3-bromo-4-methylphenyl)sulfonyl)methyl)tetrahydro-2H-pyran.
LCMS for C.sub.17H.sub.28BO.sub.5S (M+H).sup.+: calculated
m/z=355.2; found 355.2.
Step 4.
4-((3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-me-
thylphenyl)sulfonyl)butan-2-ol
[1445] The title compound was synthesized according to an
experimental procedure analogous to the synthesis of Example 492,
Step 4, substituting
3-bromo-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-8-amine for
7-bromoimidazo[2,1-][1,2,4]triazin-4-amine and substituting
4-((4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfon-
yl)butan-2-ol for
4,4,5,5-tetramethyl-2-(2-methyl-5-(((tetrahydro-2H-pyran-4-yl)methyl)sulf-
onyl)phenyl)-1,3,2-dioxaborolane. .sup.1H NMR (600 MHz,
DMSO-d.sub.6) .delta. 7.94 (dd, J=8.1, 2.0 Hz, 1H), 7.91 (d, J=1.9
Hz, 1H), 7.83 (s, 1H), 7.74 (d, J=8.1 Hz, 1H), 7.68 (br s, 3H),
4.63 (d, J=4.7 Hz, 1H), 3.62 (s, 1H), 3.41-3.28 (m, 2H), 2.28 (s,
3H), 1.70-1.50 (m, 2H), 1.02 (d, J=6.2 Hz, 3H). LCMS for
C.sub.18H.sub.20F.sub.3N.sub.4O.sub.3S (M+H).sup.+: calculated
m/z=429.1; found 429.2.
Example 495.
4-((3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphe-
nyl)sulfonyl)-2-methylbutan-2-ol
##STR00762##
[1446] Step 1.
4-((3-Bromo-4-methylphenyl)sulfonyl)-2-methylbutan-2-ol
##STR00763##
[1448] Methylmagnesium bromide (40 .mu.L, 0.1 mmol, 3 M in
Et.sub.2O) was added dropwise to a solution of
4-((3-bromo-4-methylphenyl)sulfonyl)butan-2-one (12 mg, 0.039 mmol)
in THF (1.0 mL) at -78.degree. C. The reaction mixture was stirred
overnight during which it came to rt. The reaction mixture was
cooled to 0.degree. C., and the reaction was quenched with
NH.sub.4Cl and water. The mixture was extracted with EtOAc
(3.times.). The organic layers were filtered through a plug of
Na.sub.2SO.sub.4, combined, and concentrated to afford the title
compound (8.2 mg, 65%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.07 (d, J=1.9 Hz, 1H), 7.73 (dd, J=8.0, 2.0 Hz, 1H), 7.43 (d,
J=7.9 Hz, 1H), 3.28-3.19 (m, 2H), 2.49 (s, 3H), 1.91-1.83 (m, 2H),
1.23 (s, 6H). LCMS for C.sub.12H.sub.16BrO.sub.2S (M-OH).sup.+:
calculated m/z=303.0, 305.0; found 303.0, 305.0.
Step 2.
2-Methyl-4-((4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2--
yl)phenyl)sulfonyl)butan-2-ol
##STR00764##
[1450] The title compound was synthesized according to an
experimental procedure analogous to the synthesis of Example 492,
Step 3 substituting
4-((3-bromo-4-methylphenyl)sulfonyl)-2-methylbutan-2-ol for
4-(((3-bromo-4-methylphenyl)sulfonyl)methyl)tetrahydro-2H-pyran.
LCMS for C.sub.18H.sub.28BO.sub.4S (M-OH).sup.+: calculated
m/z=351.2; found 351.1.
Step 4.
4-((3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-me-
thylphenyl)sulfonyl)-2-methylbutan-2-ol
[1451] The title compound was synthesized according to an
experimental procedure analogous to the synthesis of Example 492,
Step 4, substituting
3-bromo-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-8-amine for
7-bromoimidazo[2,1-f][1,2,4]triazin-4-amine and substituting
2-methyl-4-((4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phen-
yl)sulfonyl)butan-2-ol for
4,4,5,5-tetramethyl-2-(2-methyl-5-(((tetrahydro-2H-pyran-4-yl)methyl)sulf-
onyl)phenyl)-1,3,2-dioxaborolane. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.98-7.89 (m, 2H), 7.83 (s, 1H), 7.74 (d,
J=8.0 Hz, 1H), 7.68 (s, 3H), 4.42 (s, 1H), 3.40-3.20 (m, 2H), 2.28
(s, 3H), 1.73-1.58 (m, 2H), 1.05 (s, 6H). LCMS for
C.sub.19H.sub.22F.sub.3N.sub.4O.sub.3S (M+H).sup.+: calculated
m/z=443.1; found 443.1.
Example 496.
1-((3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphe-
nyl)sulfonyl)propan-2-ol Trifluoroacetate
##STR00765##
[1452] Step 1. 1-((3-Bromo-4-methylphenyl)sulfonyl)propan-2-one
##STR00766##
[1454] A mixture of sodium 3-bromo-4-methylbenzenesulfinate (20 mg,
0.078 mmol) and chloroacetone (6.5 .mu.L, 0.078 mmol) in DMF (230
.mu.L) was heated at 100.degree. C. for 5 min in a microwave. The
reaction mixture was diluted with water. The aqueous mixture was
extracted with EtOAc (3.times.). The organic layers were filtered
through a plug of Na.sub.2SO.sub.4, combined, and concentrated to
afford the title compound (15 mg, 64%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.04 (s, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.43 (d,
J=7.9 Hz, 1H), 4.15 (s, 2H), 2.49 (s, 3H), 2.41 (s, 3H). LCMS for
C.sub.10H.sub.15BrNO.sub.3S (M+NH.sub.4).sup.+: calculated
m/z=308.0, 310.0; found 308.0, 310.0.
Step 2. 1-((3-Bromo-4-methylphenyl)sulfonyl)propan-2-ol
##STR00767##
[1456] The title compound was synthesized according to an
experimental procedure analogous to the synthesis of Example 494,
Step 2, substituting
1-((3-bromo-4-methylphenyl)sulfonyl)propan-2-one for
4-((3-bromo-4-methylphenyl)sulfonyl)butan-2-one. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.08 (s, 1H), 7.75 (d, J=7.7 Hz, 1H), 7.44
(d, J=8.0 Hz, 1H), 4.33 (s, 1H), 3.36-3.05 (m, 3H), 2.50 (s, 3H),
1.26 (d, J=6.3 Hz, 3H). LCMS for C.sub.10H.sub.14BrO.sub.3S
(M+H).sup.+: calculated m/z=293.0, 295.0; found 293.0, 294.9.
Step 3.
1-((4-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl-
)sulfonyl)propan-2-ol
##STR00768##
[1458] The title compound was synthesized according to an
experimental procedure analogous to the synthesis of Example 492,
Step 3 substituting 1-((3-bromo-4-methylphenyl)sulfonyl)propan-2-ol
for
4-(((3-bromo-4-methylphenyl)sulfonyl)methyl)tetrahydro-2H-pyran.
LCMS for C.sub.16H.sub.26BO.sub.5S (M+H).sup.+: calculated
m/z=341.2; found 341.1.
Step 4.
1-((3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-me-
thylphenyl)sulfonyl)propan-2-ol Trifluoroacetate
[1459] The title compound was synthesized according to an
experimental procedure analogous to the synthesis of Example 492,
Step 4, substituting
3-bromo-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-8-amine for
7-bromoimidazo[2,1-f][1,2,4]triazin-4-amine and substituting
1-((4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfon-
yl)propan-2-ol for
4,4,5,5-tetramethyl-2-(2-methyl-5-(((tetrahydro-2H-pyran-4-yl)methyl)sulf-
onyl)phenyl)-1,3,2-dioxaborolane. LCMS for
C.sub.17H.sub.18F.sub.3N.sub.4O.sub.3S (M+H).sup.+: calculated
m/z=415.1; found 415.2.
Example 497.
1-((3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphe-
nyl)sulfonyl)propan-2-ol
##STR00769##
[1460] Step 1. Sodium
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylbenzenesulfinate
##STR00770##
[1462] The title compound was synthesized according to an
experimental procedure analogous to the synthesis of Example 492,
Step 1, substituting
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylbenzenesulfonyl
chloride for 3-bromo-4-methylbenzenesulfonyl chloride. LCMS for
C.sub.12H.sub.12N.sub.5O.sub.2S (M+2H).sup.+: calculated m/z=290.1;
found 290.0.
Step 2.
1-((3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-me-
thylphenyl)sulfonyl)propan-2-ol
[1463] To a solution of sodium
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylbenzenesulfinate
(15 mg, 0.048 mmol) in DMF (240 .mu.L) was added
(bromomethyl)cyclobutane (5.4 .mu.L, 0.048 mmol). The reaction
mixture was stirred at 50.degree. C. overnight. The reaction
mixture was diluted with MeOH and filtered. Purification via
preparative HPLC on a C-18 column (pH 10, 33-55% MeCN/0.1%
NH.sub.4OH (aq) over 5 min, 60 mL/min) afforded the title compound
as a white solid (7.5 mg, 44%). LCMS for
C.sub.17H.sub.20N.sub.5O.sub.2S (M+H).sup.+: calculated m/z=358.1;
found 358.2.
Example 498.
Cis-4-(((3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulf-
onyl)methyl)cyclohexan-1-ol
##STR00771##
[1465] To a solution of sodium
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylbenzenesulfinate
(17 mg, 0.055 mmol) in DMF (0.27 mL) was added
cis-(4-(bromomethyl)cyclohexyloxy)(tert-butyl)dimethylsilane (17
mg, 0.055 mmol) (prepared as described by Liu, J. et al. ACS Med.
Chem. Lett. 2012, 3, 129). The reaction mixture was stirred at
50.degree. C. overnight. After cooling to rt, an additional portion
of cis-(4-(bromomethyl)cyclohexyloxy)(tert-butyl)dimethylsilane (17
mg, 0.055 mmol) in DMF (0.10 mL) was added, and the reaction
mixture was stirred at 50.degree. C. for 1 d. The reaction mixture
was diluted with water. The aqueous mixture was extracted with
EtOAc (3.times.). The combined organic layers were washed with
brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated to
afford the unpurified TBS-protected intermediate (31 mg). LCMS for
C.sub.25H.sub.38N.sub.5O.sub.3SSi (M+H).sup.+: calculated
m/z=516.2; found 516.2.
[1466] This crude product was dissolved in MeOH (2.5 mL), and conc.
HCl (0.23 mL, 2.7 mmol, 12 M) was added. The reaction mixture was
stirred at rt for 3 h and then concentrated. Purification via
preparative HPLC on a C-18 column (pH 2, 21-33% MeCN/0.1% TFA (aq)
over 5 min, 60 mL/min) and then repurification via preparative HPLC
on a C-18 column (pH 10, 20-40% MeCN/0.1% NH.sub.4OH (aq) over 5
min, 60 mL/min) afforded the title compound (1.3 mg, 5.9%). LCMS
for C.sub.19H.sub.24N.sub.5O.sub.3S (M+H).sup.+: calculated
m/z=402.2; found 402.1.
[1467] Examples 499 to 500 were synthesized according to procedures
analogous to the synthesis of Example 492, and the data are listed
in Table 21.
TABLE-US-00025 TABLE 21 ##STR00772## Ex. LCMS No. Name R.sup.10
[M+H].sup.+ 499 7-(5-((Cyclopropylmethyl)-
sulfonyl)-2-ethylphenyl)- imidazo[2,1-f][1,2,4]triazin- 4-amine
##STR00773## 344.1 500 7-(5-(((3,3- Difluorocyclobutyl)-
methyl)sulfonyl)-2- methylphenyl)imidazo[2,1-
f][1,2,4]triazin-4-amine ##STR00774## 394.1
Example 501.
Cis-3-((3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfo-
nyl)cyclohexan-1-ol
##STR00775##
[1469] A mixture of sodium
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylbenzenesulfinate
(50 mg, 0.16 mmol) and cyclohex-2-en-1-one (17 .mu.L, 0.18 mmol) in
AcOH (37 .mu.L) and water (370 .mu.L) was heated 1 d at 110.degree.
C. After cooling to rt, the reaction mixture was diluted with
water. The aqueous mixture was extracted with EtOAc (3.times.). The
combined organic layers were washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated to afford the crude
ketone intermediate. LCMS for C.sub.18H.sub.20N.sub.5O.sub.3S
(M+H).sup.+: calculated m/z=386.1; found 386.1.
[1470] The crude ketone intermediate was dissolved in 1:1 iPrOH/THF
(4.0 mL), and the solution was cooled to 0.degree. C. Sodium
borohydride (8.5 mg, 0.23 mmol) was then added, and the reaction
mixture was stirred for 1 h at 0.degree. C. The reaction was
quenched with H.sub.2O (1 mL). Purification via preparative HPLC on
a C-18 column (pH 10, 18-38% MeCN/0.1% NH.sub.4OH (aq) over 5 min,
60 mL/min) afforded the title compound as a white solid (17 mg,
27%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.06 (s, 1H),
8.02 (s, 2H), 7.94 (d, J=2.0 Hz, 1H), 7.81 (dd, J=8.0, 2.0 Hz, 1H),
7.79 (s, 1H), 7.67 (d, J=8.2 Hz, 1H), 4.58 (d, J=4.8 Hz, 1H),
3.47-3.35 (m, 1H), 3.29-3.21 (m, 1H), 2.38 (s, 3H), 2.11 (d, J=12.2
Hz, 1H), 1.88 (d, J=11.5 Hz, 1H), 1.78 (d, J=12.7 Hz, 2H),
1.34-1.11 (m, 3H), 1.10-0.94 (m, 1H). LCMS for
C.sub.18H.sub.22N.sub.5O.sub.3S (M+H).sup.+: calculated m/z=388.1;
found 388.1.
Example 502.
3-((3-(8-Amino-6-(2-methoxypyridin-3-yl)imidazo[1,2-a]pyrazin-3-yl)-4-met-
hylphenyl)sulfonyl)-3-methylbutan-2-ol Trifluoroacetate
##STR00776##
[1471] Step 1.
3-((3-Bromo-4-methylphenyl)sulfonyl)-3-methylbutan-2-one
##STR00777##
[1473] To a mixture of
1-((3-bromo-4-methylphenyl)sulfonyl)propan-2-one (70 mg, 0.24 mmol)
(from Example 496, Step 1) and potassium carbonate (73 mg, 0.53
mmol) in DMF (2.4 mL) was added iodomethane (37 .mu.L, 0.60 mmol).
The reaction mixture was stirred at rt for 2 h. The reaction
mixture was diluted with water, and the aqueous mixture was
extracted with EtOAc (3.times.). The combined organic layers were
washed with brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated. Purification via silica gel chromatography (1-50%
EtOAc/hexanes) afforded the title compound as a white solid (42 mg,
55%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.92 (d, J=1.9 Hz,
1H), 7.57 (dd, J=8.0, 1.9 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 2.49 (s,
6H), 1.55 (s, 6H). LCMS for C.sub.12H.sub.15BrNaO.sub.3S
(M+Na).sup.+: calculated m/z=341.0, 343.0; found 340.9, 342.9.
Step 2. 3-((3-Bromo-4-methylphenyl)sulfonyl)-3-methylbutan-2-ol
##STR00778##
[1475] The title compound was synthesized according to an
experimental procedure analogous to the synthesis of Example 494,
Step 2, substituting
3-((3-bromo-4-methylphenyl)sulfonyl)-3-methylbutan-2-one for
4-((3-bromo-4-methylphenyl)sulfonyl)butan-2-one. LCMS for
C.sub.12H.sub.18BrO.sub.3S (M+H).sup.+: calculated m/z=321.0,
323.0; found 321.0, 323.0.
Step 3.
3-Methyl-3-((4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2--
yl)phenyl)sulfonyl)butan-2-ol
##STR00779##
[1477] The title compound was synthesized according to an
experimental procedure analogous to the synthesis of Example 492,
Step 3 substituting
3-((3-bromo-4-methylphenyl)sulfonyl)-3-methylbutan-2-ol for
4-(((3-bromo-4-methylphenyl)sulfonyl)methyl)tetrahydro-2H-pyran.
LCMS for C.sub.18H.sub.30BO.sub.5S (M+H).sup.+: calculated
m/z=369.2; found 369.2.
Step 4.
3-((3-(8-Amino-6-(2-methoxypyridin-3-yl)imidazo[1,2-a]pyrazin-3-yl-
)-4-methylphenyl)sulfonyl)-3-methylbutan-2-ol Trifluoroacetate
[1478] The title compound was synthesized according to an
experimental procedure analogous to the synthesis of Example 40,
Step 2, substituting
3-methyl-3-((4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phen-
yl)sulfonyl)butan-2-ol for
4,4,5,5-tetramethyl-2-[2-methyl-5-(methylsulfonyl)phenyl]-1,3,2-dioxaboro-
lane and substituting (2-methoxypyridin-3-yl)boronic acid for
(2-fluorophenyl)boronic acid. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 8.24 (s, 1H), 8.21 (dd, J=4.9, 1.9 Hz, 1H), 7.96-7.83 (m,
4H), 7.71 (d, J=8.1 Hz, 1H), 7.14 (dd, J=7.5, 4.9 Hz, 1H),
4.04-3.93 (m, 1H), 3.88 (s, 3H), 2.36 (s, 3H), 1.19 (d, J=4.1 Hz,
6H), 1.10 (d, J=6.3 Hz, 3H). LCMS for
C.sub.24H.sub.28N.sub.5O.sub.4S (M+H).sup.+: calculated m/z=482.2;
found 482.1.
Example 503.
1-(((3-(8-Amino-6-(3-fluoropyridin-4-yl)imidazo[1,2-a]pyrazin-3-yl)-4-met-
hylphenyl)sulfonyl)methyl)cyclobutan-1-ol
##STR00780##
[1479] Step 1.
1-(((3-Bromo-4-methylphenyl)sulfonyl)methyl)cyclobutan-1-ol
##STR00781##
[1481] To a solution of 2-bromo-1-methyl-4-(methylsulfonyl)benzene
(50 mg, 0.20 mmol) in THF (1.0 mL) at -78.degree. C. was added
dropwise n-butyllithium (80 .mu.L, 0.20 mmol, 2.5 M in hexanes),
and the reaction mixture was stirred at -78.degree. C. for 30 min.
The reaction mixture was then added dropwise to a solution of
cyclobutanone (16 .mu.L, 0.22 mmol) in THF (2.0 mL) at -78.degree.
C. After 10 min, the -78.degree. C. bath was removed, and the
reaction mixture was stirred for 4 h, during which it came to rt.
The reaction mixture was then cooled to 0.degree. C., and the
reaction was quenched with sat. NH.sub.4C.sub.1. The mixture was
partitioned between water and DCM. The organic layer was removed,
and the aqueous layer was extracted with DCM (2.times.). The
combined organic layers were dried over Na.sub.2SO.sub.4, filtered,
and concentrated. Purification via preparative HPLC on a C-18
column (pH 2, 26-51% MeCN/0.1% TFA (aq) over 5 min, 60 mL/min)
afforded the title compound as a white solid (11 mg, 14%). .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 8.08 (d, J=1.9 Hz, 1H), 7.76 (dd,
J=7.9, 1.9 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 3.46 (s, 2H), 2.50 (s,
4H), 2.37-2.07 (m, 3H), 2.04-1.78 (m, 1H), 1.78-1.49 (m, 1H). LCMS
for C.sub.12H.sub.19BrNO.sub.3S (M+NH.sub.4).sup.+: calculated
m/z=336.0, 338.0; found 336.0, 338.0.
Step 2.
1-(((4-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pheny-
l)sulfonyl)methyl)cyclobutan-1-ol
##STR00782##
[1483] The title compound was synthesized according to an
experimental procedure analogous to the synthesis of Example 492,
Step 3, substituting
1-(((3-bromo-4-methylphenyl)sulfonyl)methyl)cyclobutan-1-ol for
4-(((3-bromo-4-methylphenyl)sulfonyl)methyl)tetrahydro-2H-pyran.
LCMS for C.sub.11H.sub.26BO.sub.4S (M-OH).sup.+: calculated
m/z=349.2; found 349.1.
Step 3.
1-(((3-(8-Amino-6-(3-fluoropyridin-4-yl)imidazo[1,2-a]pyrazin-3-yl-
)-4-methylphenyl)sulfonyl)methyl)cyclobutan-1-ol
[1484] The title compound was synthesized according to an
experimental procedure analogous to the synthesis of Example 40,
Step 2, substituting
1-(((4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfo-
nyl)methyl)cyclobutan-1-ol for
4,4,5,5-tetramethyl-2-[2-methyl-5-(methylsulfonyl)phenyl]-1,3,2-dioxaboro-
lane and substituting
3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine
for (2-fluorophenyl)boronic acid. LCMS for
C.sub.23H.sub.23FN.sub.5O.sub.3S (M+H).sup.+: calculated m/z=468.1;
found 468.1.
Example 504.
3-(8-Amino-6-isopropylimidazo[1,2-a]pyrazin-3-yl)-N-(trans-4-hydroxycyclo-
hexyl)-4-methylbenzenesulfonamide
##STR00783##
[1486] The title compound was synthesized according to experimental
procedures analogous to the synthesis of Example 38, substituting
potassium isopropenyltrifluoroborate for potassium
vinyltrifluoroborate in Step 1. LCMS for
C.sub.22H.sub.30N.sub.5O.sub.3S (M+H).sup.+: calculated m/z=444.2;
found 444.2.
Example 505.
3-(8-Amino-6-methylimidazo[1,2-a]pyrazin-3-yl)-N-((1r,4r)-4-hydroxy-4-met-
hylcyclohexyl)-4-methylbenzenesulfonamide
##STR00784##
[1487] Step 1.
N-((1r,4r)-4-Hydroxy-4-methylcyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl--
1,3,2-dioxaborolan-2-yl)benzenesulfonamide
##STR00785##
[1489] The title compound was synthesized according to experimental
procedures analogous to the synthesis of Example 1, Steps 1 and 2,
substituting trans-4-amino-1-methylcyclohexanol for
trans-4-aminocyclohexanol in Step 1. LCMS for
C.sub.20H.sub.33BNO.sub.5S (M+H).sup.+: calculated m/z=410.2; found
410.2.
Step 2. 3-Iodo-6-methylimidazo[1,2-a]pyrazin-8-amine
##STR00786##
[1491] The title compound was synthesized according to experimental
procedures analogous to the synthesis of Example 16, Steps 1 and 2,
substituting 8-bromo-6-methylimidazo[1,2-a]pyrazine (Frontier,
B12886) for 6,8-dibromoimidazo[1,2-a]pyrazine in Step 1. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 7.58 (s, 1H), 7.38 (s, 1H),
6.95 (s, 2H), 2.23 (s, 3H). LCMS for C.sub.7H.sub.8IN.sub.4
(M+H).sup.+: calculated m/z=275.0; found 275.0.
Step 3.
3-(8-Amino-6-methylimidazo[1,2-a]pyrazin-3-yl)-N-((r,4r)-4-hydroxy-
-4-methylcyclohexyl)-4-methylbenzenesulfonamide
[1492] The title compound was synthesized according to an
experimental procedure analogous to the synthesis of Example 1,
Step 3, substituting
N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl--
1,3,2-dioxaborolan-2-yl)benzenesulfonamide for
N-(trans-4-hydroxycyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxa-
borolan-2-yl)benzenesulfonamide and substituting
3-iodo-6-methylimidazo[1,2-a]pyrazin-8-amine for
3-bromoimidazo[1,2-a]pyridin-8-amine. .sup.1H NMR (600 MHz,
DMSO-d.sub.6) .delta. 7.83 (dd, J=8.1, 2.0 Hz, 1H), 7.75 (d, J=2.0
Hz, 1H), 7.64 (d, J=8.2 Hz, 1H), 7.61 (s, 1H), 7.60 (s, 1H), 7.00
(d, J=0.9 Hz, 1H), 6.98 (s, 2H), 4.12 (s, 1H), 3.09 (s, 1H), 2.23
(s, 3H), 2.15 (d, J=0.8 Hz, 3H), 1.66-1.55 (m, 2H), 1.52-1.43 (m,
2H), 1.32-1.17 (m, 4H), 1.05 (s, 3H). LCMS for
C.sub.22H.sub.28N.sub.5O.sub.3S (M+H).sup.+: calculated m/z=430.2;
found 430.2.
Example 506.
(S)-1-((3-(8-Amino-6-(2-fluoro-4-(hydroxymethyl)phenyl)imidazo[1,2-a]pyra-
zin-3-yl)-4-methylphenyl)sulfonyl)pyrrolidin-3-ol
##STR00787##
[1493] Step 1.
(S)-1-((4-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)su-
lfonyl)pyrrolidin-3-ol
##STR00788##
[1495] The title compound was synthesized according to experimental
procedures analogous to the synthesis of Example 1, Steps 1 and 2,
substituting (S)-pyrrolidin-3-ol for trans-4-aminocyclohexanol in
Step 1. LCMS for C.sub.17H.sub.27BNO.sub.5S (M+H).sup.+: calculated
m/z=368.2; found 368.1.
Step 2.
(S)-1-((3-(8-Amino-6-bromoimidazo[1,2-a]pyrazin-3-yl)-4-methylphen-
yl)sulfonyl)pyrrolidin-3-ol
##STR00789##
[1497] The title compound was synthesized according to an
experimental procedure analogous to the synthesis of Example 16,
Step 3, substituting
(S)-1-((4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)su-
lfonyl)pyrrolidin-3-ol for
N-(trans-4-hydroxycyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxa-
borolan-2-yl)benzenesulfonamide. LCMS for
C.sub.17H.sub.19BrN.sub.5O.sub.3S (M+H).sup.+: calculated
m/z=452.0, 454.0; found 452.1, 454.1.
Step 3.
(S)-1-((3-(8-Amino-6-(2-fluoro-4-(hydroxymethyl)phenyl)imidazo[1,2-
-a]pyrazin-3-yl)-4-methylphenyl)sulfonyl)pyrrolidin-3-ol
[1498] The title compound was synthesized according to an
experimental procedure analogous to the synthesis of Example 17,
substituting
(S)-1-((3-(8-amino-6-bromoimidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)sulf-
onyl)pyrrolidin-3-ol for
3-(8-amino-6-bromoimidazo[1,2-a]pyrazin-3-yl)-N-(trans-4-hydroxycyclohexy-
l)-4-methylbenzenesulfonamide and substituting
(2-fluoro-4-(hydroxymethyl)phenyl)boronic acid for
(2-methylphenyl)boronic acid. LCMS for
C.sub.24H.sub.25FN.sub.5O.sub.4S (M+H).sup.+: calculated m/z=498.2;
found 498.2.
Example 507.
3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-((1s,4s)-4-hydroxy-4-methy-
lcyclohexyl-1-d)-4-methylbenzenesulfonamide
##STR00790##
[1499] Step 1.
(R)-2-Methyl-N-(8-deutero-1,4-dioxaspiro[4.5]decan-8-yl)propane-2-sulfina-
mide
##STR00791##
[1501] A mixture of 1,4-dioxaspiro[4.5]decan-8-one (2.5 g, 16
mmol), (R)-(+)-2-methyl-2-propanesulfinamide (1.9 g, 16 mmol), and
titanium(IV) ethoxide (6.7 ml, 32 mmol) in THF (32 mL) was heated
at reflux for 2 h. After cooling to rt, the reaction mixture was
added dropwise via cannula to a suspension of sodium borodeuteride
(2.0 g, 48 mmol) (Aldrich, 205591) in THF (12 mL) at -44.degree. C.
The original flask, which had contained the reaction mixture from
the imine condensation, was rinsed with THF (2.times.6 mL), and
this mixture was added dropwise to the flask containing the sodium
borodeuteride reaction mixture. The reaction mixture was then
allowed to warm to rt, stirring for 3 h. The reaction mixture was
cooled to 0.degree. C., and the reaction quenched by dropwise
addition of methanol (13 mL, 320 mmol). After stirring for 10 min,
the mixture was warmed to rt while stirring 30 min. The mixture was
then diluted with EtOAc (80 mL) and poured into brine (5 mL). The
resulting slurry was stirred rapidly for 20 min. The slurry was
filtered through Celite, rinsing the filter cake generously with
EtOAc. The filtrate was then concentrated. Purification via silica
gel chromatography (3-7% MeOH in DCM) afforded the title compound
as a white solid (3.8 g, 90%). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 3.94 (s, 4H), 3.00 (s, 1H), 2.05-1.90 (m, 2H), 1.83-1.70
(m, 2H), 1.68-1.51 (m, 4H), 1.20 (s, 9H). LCMS for
C.sub.12H.sub.23DNO.sub.3S (M+H).sup.+: calculated m/z=263.2; found
263.1.
Step 2.
(R)-2-Methyl-N-(1-deutero-4-oxocyclohexyl)propane-2-sulfinamide
##STR00792##
[1503] A solution of p-toluenesulfonic acid monohydrate (0.13 g,
0.71 mmol) in water (4.9 mL) was added to a solution of
((R)-2-methyl-N-(8-deutero-1,4-dioxaspiro[4.5]decan-8-yl)propane-2-sulfin-
amide (3.7 g, 14 mmol) in acetone (9.8 mL). The reaction mixture
was then heated at 100.degree. C. for 15 min in a microwave. The
reaction mixture was diluted with EtOAc and washed with sat.
NaHCO.sub.3. The organic layer was removed, and the aqueous layer
was extracted with EtOAc (2.times.). The combined organic layers
were dried over Na.sub.2SO.sub.4, filtered, and concentrated.
Purification via silica gel chromatography (70-100% EtOAc in DCM,
then 0-5% MeOH in EtOAc) afforded the title compound as an
off-white solid (2.3 g, 75%). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 3.12 (s, 1H), 2.55-2.30 (m, 4H), 2.30-2.14 (m, 2H),
1.98-1.75 (m, 2H), 1.24 (s, 9H). LCMS for
C.sub.10H.sub.19DNO.sub.2S (M+H).sup.+: calculated m/z=219.1; found
219.1.
Step 3.
(R)-N-((1r,4R)-4-hydroxy-4-methylcyclohexyl-1-d)-2-methylpropane-2-
-sulfinamide and
(R)-N-((1s,4S)-4-hydroxy-4-methylcyclohexyl-1-d)-2-methylpropane-2-sulfin-
amide
##STR00793##
[1505] To a solution of
(R)-2-methyl-N-(1-deutero-4-oxocyclohexyl)propane-2-sulfinamide
(1.0 g, 4.6 mmol) in THF (46 mL) at -78.degree. C. was added
dropwise methyllithium (8.6 mL, 14 mmol, 1.6 M in diethyl ether).
Upon addition, the reaction mixture was allowed to come to rt and
was stirred for 3 h at rt. The reaction mixture was cooled to
0.degree. C., and the reaction was quenched with sat. NH.sub.4Cl
solution (20 mL). The bath was removed. After stirring for 5 min,
the mixture was then partitioned between water and EtOAc. The
organic layer was removed, and the aqueous layer was extracted with
EtOAc (2.times.). The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered, and concentrated. Purification via
silica gel chromatography (1-12% MeOH in DCM) afforded a mixture of
the title compounds as a white solid (0.30 g). Repurification via
preparative HPLC on a C-18 column (pH 10, 14-28% MeCN/0.1%
NH.sub.4OH (aq) over 5 min, 60 mL/min) afforded the separated
isomers:
(R)-N-((1r,4R)-4-hydroxy-4-methylcyclohexyl-1-d)-2-methylpropane-2-sulfin-
amide (first eluting, t.sub.R=4.86 min, minor isomer) as white
solid (53 mg, 4.9%) and
(R)-N-((1s,4S)-4-hydroxy-4-methylcyclohexyl-1-d)-2-methylpropane-2-sulfin-
amide (second eluting, t.sub.R=5.62 min, major isomer) as a white
solid (0.12 g, 11%). First eluting: LCMS for
C.sub.11H.sub.23DNO.sub.2S (M+H).sup.+: calculated m/z=235.2; found
235.2. Second eluting: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
3.04 (br s, 1H), 1.91-1.78 (m, 2H), 1.76-1.34 (m, 8H), 1.23 (s,
3H), 1.20 (s, 9H). LCMS for C.sub.IIH.sub.23DNO.sub.2S (M+H).sup.+:
calculated m/z=235.2; found 235.1.
Step 4. (1s,4s)-4-Amino-1-methylcyclohexan-4-d-1-ol
Hydrochloride
##STR00794##
[1507] To a solution of
(R)-N-((1s,4S)-4-hydroxy-4-methylcyclohexyl-1-d)-2-methylpropane-2-sulfin-
amide (10 mg, 0.043 mmol) in MeOH (0.50 mL) was added HCl (50
.mu.L, 0.2 mmol, 4.0 M in 1,4-dioxane) while the reaction flask was
in a rt water bath. The bath was removed, and the reaction mixture
was stirred at rt for 30 min. The reaction mixture was concentrated
to afford the title compound. .sup.1H NMR (600 MHz, DMSO-d.sub.6)
.delta. 8.10 (s, 3H), 1.70-1.62 (m, 4H), 1.55 (d, J=11.7 Hz, 2H),
1.35-1.25 (m, 2H), 1.09 (s, 3H). LCMS for C.sub.7H.sub.15DNO
(M+H).sup.+: calculated m/z=131.1; found 131.2.
Step 5.
3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-((1s,4s)-4-hydroxy--
4-methylcyclohexyl-1-d)-4-methylbenzenesulfonamide
[1508] To a solution of (1s,4s)-4-amino-1-methylcyclohexan-4-d-1-ol
hydrochloride (7.1 mg, 0.043 mmol), triethylamine (18 .mu.L, 0.128
mmol), and DMAP (0.5 mg, 4 .mu.mol) in DMA (350 .mu.L) at 0.degree.
C. was added
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylbenzenesulfonyl
chloride (14 mg, 0.043 mmol) in a single portion. The reaction
mixture was allowed to come to rt, stirring for 2 h. The reaction
mixture was again cooled to 0.degree. C., and the reaction was
quenched with MeOH. Purification via preparative HPLC on a C-18
column (pH 10, 26-38% MeCN/0.1% NH.sub.4OH (aq) over 5 min, 60
mL/min) afforded the title compound as a white solid (4.1 mg, 23%).
LCMS for C.sub.19H.sub.24DN.sub.6O.sub.3S (M+H).sup.+: calculated
m/z=418.2; found 418.1.
Example 508.
3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-((1r,4r)-4-hydroxy-4-methy-
lcyclohexyl-1-d)-4-methylbenzenesulfonamide Trifluoroacetate
##STR00795##
[1509] Step 1. (1r,4r)-4-Amino-1-methylcyclohexan-4-d-1-ol
Hydrochloride
##STR00796##
[1511] The title compound was synthesized according to experimental
procedures analogous to the synthesis of Example 507, Step 4
substituting
(R)-N-((1r,4R)-4-hydroxy-4-methylcyclohexyl-1-d)-2-methylpropane-2-sulfin-
amide (from Example 507, Step 3) for
(R)-N-((1s,4S)-4-hydroxy-4-methylcyclohexyl-1-d)-2-methylpropane-2-sulfin-
amide. LCMS for C.sub.7H.sub.15DNO (M+H).sup.+: calculated
m/z=131.1; found 131.1.
Step 2.
3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-((1r,4r)-4-hydroxy--
4-methylcyclohexyl-1-d)-4-methylbenzenesulfonamide
Trifluoroacetate
[1512] The title compound was synthesized according to experimental
procedures analogous to the synthesis of Example 507, Step 5
substituting (1r,4r)-4-amino-1-methylcyclohexan-4-d-1-ol
hydrochloride for (1s,4s)-4-amino-1-methylcyclohexan-4-d-1-ol
hydrochloride. .sup.1H NMR (500 MHz, CD.sub.3CN) .delta. 8.07 (s,
1H), 7.96 (d, J=2.0 Hz, 1H), 7.83 (dd, J=8.1, 2.1 Hz, 1H), 7.70 (s,
1H), 7.56 (d, J=8.1 Hz, 1H), 6.99 (br s, 2H), 5.66 (s, 1H), 2.35
(s, 3H), 1.77-1.64 (m, 2H), 1.58-1.46 (m, 2H), 1.44-1.27 (m, 4H),
1.12 (s, 3H). LCMS for C.sub.19H.sub.24DN.sub.6O.sub.3S
(M+H).sup.+: calculated m/z=418.2; found 418.2.
Example 509. Ethyl
1-((3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphe-
nyl)sulfonyl)piperidine-3-carboxylate
##STR00797##
[1513] Step 1. Ethyl
1-((4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfon-
yl)piperidine-3-carboxylate
##STR00798##
[1515] The title compound was synthesized according to experimental
procedures analogous to the synthesis of Example 1, Steps 1 and 2,
substituting ethyl piperidine-3-carboxylate for
trans-4-aminocyclohexanol in Step 1. LCMS for
C.sub.21H.sub.33BNO.sub.6S (M+H).sup.+: calculated m/z=438.2; found
438.2.
Step 2. Ethyl
1-((3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphe-
nyl)sulfonyl)piperidine-3-carboxylate
[1516] The title compound was synthesized according to an
experimental procedure analogous to the synthesis of Example 1,
Step 3, substituting ethyl
1-((4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-
sulfonyl)piperidine-3-carboxylate for
N-(trans-4-hydroxycyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxa-
borolan-2-yl)benzenesulfonamide and substituting
3-bromo-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-8-amine for
3-bromoimidazo[1,2-a]pyridin-8-amine. LCMS for
C.sub.22H.sub.25F.sub.3N.sub.5O.sub.4S (M+H).sup.+: calculated
m/z=512.2; found 512.2.
Example 510.
1-((3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphe-
nyl)sulfonyl)piperidine-3-carboxylic Acid Trifluoroacetate
##STR00799##
[1518] To a solution of ethyl
1-((3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphe-
nyl)sulfonyl)piperidine-3-carboxylate (22 mg, 0.043 mmol) in THF
(0.31 mL) was added 1.0 M sodium hydroxide (95 .mu.L, 0.095 mmol).
The reaction mixture was stirred overnight at rt; diluted with
MeOH, MeCN, and water; and filtered. Purification via preparative
HPLC on a C-18 column (pH 2, 33-53% MeCN/0.1% TFA (aq) over 5 min,
60 mL/min) afforded the title compound as a white solid (7.7 mg,
30%). LCMS for C.sub.20H.sub.21F.sub.3N.sub.5O.sub.4S (M+H).sup.+:
calculated m/z=484.1; found 484.1.
Example 511.
(1-((3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylph-
enyl)sulfonyl)piperidin-3-yl)((R)-2-(methoxymethyl)pyrrolidin-1-yl)methano-
ne
##STR00800##
[1520] To a mixture of (R)-2-(methoxymethyl)pyrrolidine (5 .mu.L,
0.04 mmol),
1-((3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-me-
thylphenyl)sulfonyl)piperidine-3-carboxylic acid (10 mg, 0.021
mmol), and N,N,N,N-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium
hexafluorophosphate (9.4 mg, 0.026 mmol) in DMF (0.20 mL) was added
dropwise N,N-diisopropylethylamine (5.0 .mu.L, 0.029 mmol). The
reaction mixture was stirred 1 h at rt. The reaction mixture was
diluted with MeOH and purified via preparative HPLC on a C-18
column (pH 10, 35-55% MeCN/0.1% NH.sub.4OH (aq) over 5 min, 60
mL/min) to afford the title compound (2.9 mg, 24%). LCMS for
C.sub.26H.sub.32F.sub.3N.sub.6O.sub.4S (M+H).sup.+: calculated
m/z=581.2; found 581.3.
Example 512. tert-Butyl
((1-((3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylp-
henyl)sulfonyl)piperidin-3-yl)methyl)carbamate
##STR00801##
[1522] The title compound was synthesized according to experimental
procedures analogous to the synthesis of Example 472, Step 9
substituting tert-butyl (piperidin-3-ylmethyl)carbamate for
piperidin-3-ylmethanol. LCMS for
C.sub.25H.sub.31F.sub.3N.sub.6NaO.sub.4S (M+Na).sup.+: calculated
m/z=591.2; found 591.3.
Example 513.
3-(5-((3-(Aminomethyl)piperidin-1-yl)sulfonyl)-2-methylphenyl)-6-(trifluo-
romethyl)imidazo[1,2-a]pyrazin-8-amine Trifluoroacetate
##STR00802##
[1524] A solution of tert-butyl
((1-((3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylp-
henyl)sulfonyl)piperidin-3-yl)methyl)carbamate (40. mg, 0.070 mmol)
in trifluoroacetic acid (1.1 mL) was stirred at rt for 1 h. The
reaction mixture was diluted with DCM and concentrated to afford
the crude product. A quarter of the crude product was purified via
preparative HPLC on a C-18 column (pH 2, 36-56% MeCN/0.1% TFA (aq)
over 5 min, 60 mL/min) to afford the title compound as a pink solid
(13 mg). LCMS for C.sub.20H.sub.24F.sub.3N.sub.6O.sub.2S
(M+H).sup.+: calculated m/z=469.2; found 469.3.
Example 514.
N-((1-((3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methy-
lphenyl)sulfonyl)piperidin-3-yl)methyl)-2-(dimethylamino)acetamide
##STR00803##
[1526] The title compound was synthesized according to experimental
procedures analogous to the synthesis of Example 511, substituting
3-(5-((3-(aminomethyl)piperidin-1-yl)sulfonyl)-2-methylphenyl)-6-(trifluo-
romethyl)imidazo[1,2-a]pyrazin-8-amine trifluoroacetate for
(R)-2-(methoxymethyl)pyrrolidine and substituting dimethylglycine
for 1-((3-(8-amino-6-(trifluoromethyl)imidazo
[1,2-a]pyrazin-3-yl)-4-methylphenyl)sulfonyl)piperidine-3-carboxylic
acid. LCMS for C.sub.24H.sub.31F.sub.3N.sub.7O.sub.3S (M+H).sup.+:
calculated m/z=554.2; found 554.1.
Example 515. tert-Butyl
(1-((3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylph-
enyl)sulfonyl)piperidin-3-yl)carbamate
##STR00804##
[1528] The title compound was synthesized according to experimental
procedures analogous to the synthesis of Example 472, Step 9
substituting tert-butyl (piperidin-3-ylmethyl)carbamate for
piperidin-3-ylmethanol. LCMS for
C.sub.24H.sub.29F.sub.3N.sub.6NaO.sub.4S (M+Na).sup.+: calculated
m/z=577.2; found 577.1.
Example 516.
3-(5-((3-Aminopiperidin-1-yl)sulfonyl)-2-methylphenyl)-6-(trifluoromethyl-
)imidazo[1,2-a]pyrazin-8-amine Trifluoroacetate
##STR00805##
[1530] The title compound was synthesized according to experimental
procedures analogous to the synthesis of Example 513, substituting
tert-butyl
(1-((3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylph-
enyl)sulfonyl)piperidin-3-yl)carbamate for tert-butyl
((1-((3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylp-
henyl)sulfonyl)piperidin-3-yl)methyl)carbamate. LCMS for
C.sub.19H.sub.22F.sub.3N.sub.6O.sub.2S (M+H).sup.+: calculated
m/z=455.1; found 455.1.
Example 517.
N-(1-((3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methyl-
phenyl)sulfonyl)piperidin-3-yl)cyclopropanecarboxamide
Trifluoroacetate
##STR00806##
[1532] The title compound was synthesized according to experimental
procedures analogous to the synthesis of Example 511, substituting
3-(5-((3-aminopiperidin-1-yl)sulfonyl)-2-methylphenyl)-6-(trifluoromethyl-
)imidazo[1,2-a]pyrazin-8-amine trifluoroacetate for
(R)-2-(methoxymethyl)pyrrolidine and substituting
cyclopropanecarboxylic acid for
1-((3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4--
methylphenyl)sulfonyl)piperidine-3-carboxylic acid. .sup.1H NMR
(600 MHz, DMSO-d.sub.6) .delta. 8.02 (d, J=7.6 Hz, 1H), 7.84 (s,
1H), 7.79 (dd, J=8.0, 2.0 Hz, 1H), 7.76 (d, J=2.0 Hz, 1H), 7.71 (d,
J=8.2 Hz, 1H), 7.69 (s, 1H), 7.66 (br s, 2H), 3.85-3.66 (m, 1H),
3.53-3.37 (m, 1H), 3.37-3.27 (m, 1H), 2.63-2.54 (m, 1H), 2.35-2.26
(m, 1H), 2.29 (s, 3H), 1.82-1.73 (m, 1H), 1.73-1.65 (m, 1H),
1.58-1.45 (m, 2H), 1.32-1.19 (m, 1H), 0.72-0.57 (m, 4H). LCMS for
C.sub.23H.sub.26F.sub.3N.sub.6O.sub.3S (M+H).sup.+: calculated
m/z=523.2; found 523.2.
Example 518.
3-(8-Aminoimidazo[1,2-b]pyridazin-3-yl)-N-((1r,4r)-4-hydroxy-4-methylcycl-
ohexyl)-4-methylbenzenesulfonamide
##STR00807##
[1533] Step 1. 3-Bromo-6-chloroimidazo[1,2-b]pyridazin-8-amine
##STR00808##
[1535] The title compound was synthesized according to an
experimental procedure analogous to Example 16, Step 2 substituting
3,8-dibromo-6-chloroimidazo[1,2-b]pyridazine (AstaTech, 50987) for
6,8-dibromoimidazo[1,2-a]pyrazine. LCMS for
C.sub.6H.sub.5BrClN.sub.4 (M+H).sup.+: calculated m/z 10=246.9,
248.9; found 247.0, 249.0.
Step 2.
3-(8-Amino-6-chloroimidazo[1,2-b]pyridazin-3-yl)-N-((1r,4r)-4-hydr-
oxy-4-methylcyclohexyl)-4-methylbenzenesulfonamide
##STR00809##
[1537] The title compound was synthesized according to an
experimental procedure analogous to Example 1, Step 3, substituting
3-bromo-6-chloroimidazo[1,2-b]pyridazin-8-amine for
3-bromoimidazo[1,2-a]pyridin-8-amine and substituting
N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl--
1,3,2-dioxaborolan-2-yl)benzenesulfonamide for
N-(trans-4-hydroxycyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxa-
borolan-2-yl)benzenesulfonamide. LCMS for
C.sub.20H.sub.25ClN.sub.5O.sub.3S (M+H).sup.+: calculated
m/z=450.1; found 450.2.
Step 3.
3-(8-Aminoimidazo[1,2-b]pyridazin-3-yl)-N-((1r,4r)-4-hydroxy-4-met-
hylcyclohexyl)-4-methylbenzenesulfonamide
[1538] To a solution of
3-(8-amino-6-chloroimidazo[1,2-b]pyridazin-3-yl)-N-((1r,4r)-4-hydroxy-4-m-
ethylcyclohexyl)-4-methylbenzenesulfonamide (12 mg, 0.027 mmol) and
triethylamine (7.4 .mu.L, 0.053 mmol) in MeOH (0.43 mL) under a
N.sub.2 atmosphere was added Pd/C (11 mg, 5.3 .mu.mol, 10% Pd,
.about.50% H.sub.2O) (Sigma-Aldrich 330108, lot 03014DC). The
atmosphere was replaced with H.sub.2. After stirring overnight at
rt, the reaction mixture was filtered through Celite, and the
Celite pad was washed with MeOH. The filtrate was concentrated.
Purification via preparative HPLC on a C-18 column (pH 10, 23-37%
MeCN/0.1% NH.sub.4OH (aq) over 5 min, 60 mL/min) afforded the title
compound as a white solid (3.0 mg, 27%). .sup.1H NMR (600 MHz,
DMSO-d.sub.6) .delta. 7.97 (d, J=5.4 Hz, 1H), 7.92 (d, J=2.1 Hz,
1H), 7.75 (dd, J=8.0, 2.1 Hz, 1H), 7.68 (s, 1H), 7.56 (d, J=8.3 Hz,
1H), 7.04 (s, 2H), 6.18 (d, J=5.4 Hz, 1H), 4.12 (s, 1H), 3.11-2.98
(m, 1H), 2.30 (s, 3H), 1.66-1.56 (m, 2H), 1.48 (t, J=8.9 Hz, 2H),
1.34-1.20 (m, 4H), 1.05 (s, 3H). LCMS for
C.sub.20H.sub.26N.sub.5O.sub.3S (M+H).sup.+: calculated m/z=416.1;
found 416.2.
Example 519.
3-(8-(Benzylamino)-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-N-(2-hy-
droxy-2-methylpropyl)-4-methylbenzenesulfonamide
##STR00810##
[1539] Step 1.
8-Chloro-3-iodo-6-(trifluoromethyl)imidazo[1,2-a]pyrazine
##STR00811##
[1541] The title compound was synthesized according to an
experimental procedure analogous to Example 472, Step 4,
substituting N-iodosuccinimide for N-bromosuccinimide. LCMS for
C.sub.7H.sub.3CF.sub.3IN.sub.3 (M+H).sup.+: calculated m/z=347.9;
found 347.9.
Step 2.
N-Benzyl-3-iodo-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-8-amine
##STR00812##
[1543] The title compound was synthesized according to an
experimental procedure analogous to Example 472, Step 5,
substituting benzylamine for 4-methoxybenzylamine and substituting
8-chloro-3-iodo-6-(trifluoromethyl)imidazo[1,2-a]pyrazine for
3-bromo-8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyrazine. LCMS
for C.sub.14H.sub.11F.sub.3IN.sub.4 (M+H).sup.+: calculated
m/z=419.0; found 419.0.
Step 3.
N-(2-hydroxy-2-methylpropyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-
-dioxaborolan-2-yl)benzenesulfonamide
##STR00813##
[1545] The title compound was synthesized according to experimental
procedures analogous to Example 1, Steps 1 and 2, substituting
1-amino-2-methylpropan-2-ol for trans-4-aminocyclohexanol in Step
1. LCMS for C.sub.17H.sub.27BNO.sub.4S (M-OH).sup.+: calculated
m/z=352.2; found 352.1.
Step 4.
3-(8-(Benzylamino)-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)--
N-(2-hydroxy-2-methylpropyl)-4-methylbenzenesulfonamide
[1546] The title compound was synthesized according to an
experimental procedure analogous to Example 1, Step 3, substituting
N-benzyl-3-iodo-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-8-amine
for 3-bromoimidazo[1,2-a]pyridin-8-amine and substituting
N-(2-hydroxy-2-methylpropyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxab-
orolan-2-yl)benzenesulfonamide for
N-(trans-4-hydroxycyclohexyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxa-
borolan-2-yl)benzenesulfonamide. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.78 (t, J=6.3 Hz, 1H), 7.84 (d, J=8.0 Hz,
1H), 7.81 (s, 2H), 7.65 (d, J=8.1 Hz, 1H), 7.62 (s, 1H), 7.51 (s,
1H), 7.43 (d, J=7.4 Hz, 2H), 7.31 (t, J=7.6 Hz, 2H), 7.23 (t, J=7.3
Hz, 1H), 4.70 (d, J=6.3 Hz, 2H), 4.38 (s, 1H), 2.65 (s, 2H), 2.25
(s, 3H), 1.04 (s, 6H). LCMS for
C.sub.25H.sub.27F.sub.3N.sub.5O.sub.3S (M+H).sup.+: calculated
m/z=534.2; found 534.1.
Example 520.
3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(5-cyanobicyclo[3.1.1]hept-
an-1-yl)-4-methylbenzenesulfonamide Trifluoroacetate
##STR00814##
[1547] Step 1. tert-butyl
(5-carbamoylbicyclo[3.1.1]heptan-1-yl)carbamate
##STR00815##
[1549] A mixture of
5-((tert-butoxycarbonyl)amino)bicyclo[3.1.1]heptane-1-carboxylic
acid (40 mg, 0.157 mmol), ammonium carbonate (75 mg, 0.78 mmol),
HATU (89 mg, 0.24 mmol), and DIEA (0.055 mL, 0.31 mmol) in DCE (0.6
mL) was stirred at ambient temperature for 5 h. The reaction
mixture was diluted with ethyl acetate (20 mL) and water (3 mL).
The layers were separated and the organic layer was washed with
water (3.times.3 mL) and the combined aqueous phases were extracted
with ethyl acetate (5 mL). The combined organic layers were washed
with brine (5 mL), dried over Na.sub.2SO.sub.4, filtered and
concentrated in-vacuo. The crude product was used directly in the
next step without further purification. LCMS for
C.sub.13H.sub.22N.sub.2O.sub.3 (M+Na).sup.+: calculated m/z=277.3;
found 277.2.
Step 2. 5-aminobicyclo[3.1.I]heptane-1-carbonitrile
Hydrochloride
##STR00816##
[1551] To a 0.degree. C. solution of tert-butyl
(5-carbamoylbicyclo[3.1.1]heptan-1-yl)carbamate (40. mg, 0.16 mmol)
and trimethylamine (0.088 mL, 0.63 mmol) was added trifluoroacetic
anhydride (0.027 mL, 0.19 mmol) and the resulting solution was
stirred at ambient temperature for 4 h. LCMS data indicated the
presence of starting material, so a second aliquot of
trifluoroacetic anhydride (30 .mu.L) was added and stirring was
continued overnight. 4 N hydrogen chloride in 1,4-dioxane (1.0 mL,
4.0 mmol) was added to the crude reaction mixture to remove the Boc
protecting group and the solution was stirred overnight. The
volatiles were removed in-vacuo and the residue was placed under
high vacuum and used in the next step without further purification.
LCMS for C.sub.8H.sub.12N.sub.2(M+H).sup.+: calculated m/z=137.2;
found 137.1.
Step 3.
3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-.sup.7-yl)-N-(5-cyanobicycl-
o[3.1.I]heptan-1-yl)-4-methylbenzenesulfonamide
Trifluoroacetate
##STR00817##
[1553] To a solution of 5-aminobicyclo[3.1.1]heptane-1-carbonitrile
hydrochloride (8.4 mg, 0.049 mmol) and
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylbenzenesulfonyl
chloride (10 mg, 0.031 mmol) in DCM (0.5 mL) was added sequentially
triethylamine (0.017 mL, 0.12 mmol), and DMAP (1.5 mg, 0.012 mmol).
After 15 min., NMP (0.2 mL) was added and the resulting solution
was stirred at ambient temperature overnight. The crude reaction
mixture was diluted with MeOH and acidified by the addition of a
couple of drops of 4 N HCl (aq) and purified by preparative HPLC on
a C-18 column (pH 2, 15-35% MeCN/0.1% TFA (aq) over 5 min, 60
mL/min) to afford the title compound. LCMS for
C.sub.20H.sub.21N.sub.7O.sub.2S (M+H).sup.+: calculated m/z=424.5;
found 424.2.
Example 521.
3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(5-(1-hydroxyethyl)bicyclo-
[3.1.1]heptan-1-yl)-4-methylbenzenesulfonamide Trifluoroacetate
##STR00818##
[1554] Step 1. Tert-Butyl
(5-(methoxy(methyl)carbamoyl)bicyclo[3.1.I]heptan-1-yl)carbamate
##STR00819##
[1556] A solution of
5-((tert-butoxycarbonyl)amino)bicyclo[3.1.1]heptane-1-carboxylic
acid (200 mg, 0.78 mmol), N,O-dimethylhydroxylamine hydrochloride
(153 mg, 1.57 mmol), HATU (357 mg, 0.94 mmol), and DIEA (0.274 mL,
1.57 mmol) in DCE (4 mL) was stirred at ambient temperature
overnight. LCMS data indicated that the major reaction component
was the desired product. The reaction mixture was diluted with
EtOAc (50 mL) and H.sub.2O (5 mL). The layers were separated and
the organic layer was washed with H.sub.2O (3.times.5 mL) and the
combined aqueous phases were extracted with EtOAc (10 mL). The
combined organic layers were washed with brine (5 mL), dried over
Na.sub.2SO.sub.4, filtered, and concentrated in-vacuo. The crude
product was used directly in the next step without any further
purification. LCMS for C.sub.15H.sub.26N.sub.2O.sub.4 (M+Na).sup.+:
calculated m/z=321.4; found 321.2.
Step 2.
5-amino-N-methoxy-N-methylbicyclo[3.1.I]heptane-1-carboxamide
Hydrochloride
##STR00820##
[1558] To a solution of tert-butyl
(5-(methoxy(methyl)carbamoyl)bicyclo[3.1.1]heptan-1-yl)carbamate
(145 mg, 0.485 mmol) in THF was added 4 N HCl in 1,4-dioxane (2.0
mL, 8.0 mmol) and the solution was stirred at ambient temperature
for 4 h. The volatiles were removed in-vacuo and the residue was
placed on the high vacuum and used in the next step without further
purification. LCMS for C.sub.10H.sub.18N.sub.2O.sub.2(M+H).sup.+:
calculated m/z=199.3; found 199.2.
Step 3.
5-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)su-
lfonamido)-N-methoxy-N-methylbicyclo[3.1.1]heptane-1-carboxamide
##STR00821##
[1560] To a solution of
5-amino-N-methoxy-N-methylbicyclo[3.1.1]heptane-1-carboxamide
hydrochloride (115 mg, 0.49 mmol), triethylamine (0.172 mL, 1.24
mmol), and DMAP (3.8 mg, 0.031 mmol) in DCM (2 mL) was added
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylbenzenesulfonyl
chloride (100. mg, 0.309 mmol) and the resulting solution was
stirred at ambient temperature overnight. LCMS data indicated that
some of the amine starting material was present, so a second
aliquot of sulfonyl chloride (40 mg) and DMAP (2 mg) were added and
stirring was continued overnight. LCMS data indicated that some of
the amine starting material was present, so an additional aliquot
of sulfonyl chloride (30 mg), Et.sub.3N (100 .mu.L), NMP (100
.mu.L) and DMAP (2 mg) were added and stirring was continued for 3
h. The crude product was purified by CombiFlash chromatography (25
g silica gel column, eluting with 0-20% methanol/dichloromethane)
to afford the desired product (62 mg, 42%). LCMS for
C.sub.22H.sub.27N.sub.7O.sub.4S (M+H).sup.+: calculated m/z=486.6;
found 486.2.
Step 4.
N-(5-acetylbicyclo[3.1.l]heptan-1-yl)-3-(4-aminoimidazo[2,1-f][1,2-
,4]triazin-7-yl)-4-methylbenzenesulfonamide
##STR00822##
[1562] To a 0.degree. C. solution of
5-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonami-
do)-N-methoxy-N-methylbicyclo[3.1.1]heptane-1-carboxamide (62 mg,
0.128 mmol) in anhydrous THF (1. mL) was added 3 M methylmagnesium
bromide in Et.sub.2O (0.20 mL, 0.60 mmol) drop-wise and the
resulting solution was allowed to gradually warm to ambient
temperature. After 4 h, LCMS data indicated that the reaction was
complete. The crude reaction mixture was cooled to 0.degree. C. and
quenched by the addition of saturated ammonium chloride (aq). The
reaction mixture was diluted with EtOAc (30 mL) and washed
successively with water (2.times.3 mL) and brine (2.times.3 mL).
The organic layer was dried over Na.sub.2SO.sub.4, filtered, and
concentrated in-vacuo. The crude product was purified by CombiFlash
chromatography (12 g silica gel column, eluting with 0-15%
methanol/dichloromethane) to afford the desired product. LCMS for
C.sub.21H.sub.24N.sub.6O.sub.3S (M+H).sup.+: calculated m/z=441.5;
found 441.1.
Step 5.
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(5-(1-hydroxyethyl)-
bicyclo[3.1.1]heptan-1-yl)-4-methylbenzenesulfonamide
Trifluoroacetate
[1563] To a solution of
N-(5-acetylbicyclo[3.1.1]heptan-1-yl)-3-(4-aminoimidazo[2,1-f][1,2,4]tria-
zin-7-yl)-4-methylbenzenesulfonamide (18 mg, 0.041 mmol) in THF
(1.0 mL) was added NaBH.sub.4 (7.7 mg, 0.20 mmol) and the resulting
mixture was stirred at ambient temperature overnight. LCMS data
indicated that the major reaction component was the desired
product. The reaction mixture was diluted with MeOH and purified by
preparative HPLC on a C-18 column (pH 2, 18.7-36.7% MeCN/0.1% TFA
(aq) over 12 min, 60 mL/min) to afford the title compound. LCMS for
C.sub.21H.sub.26N.sub.6O.sub.3S (M+H).sup.+: calculated m/z=443.5;
found 443.2.
Example 522.
3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(5-(1-(3-cyanoazetidin-1-y-
l)ethyl)bicyclo[3.1.1]heptan-1-yl)-4-methylbenzenesulfonamide
Trifluoroacetate
##STR00823##
[1565] To a pre-stirred solution of
N-(5-acetylbicyclo[3.1.1]heptan-1-yl)-3-(4-aminoimidazo[2,1-f][1,2,4]tria-
zin-7-yl)-4-methylbenzenesulfonamide (18 mg, 0.041 mmol, prepared
in Example 521, Step 4), azetidine-3-carbonitrile hydrochloride (24
mg, 0.20 mmol), and Et.sub.3N (0.028 mL, 0.20 mmol) was added
sodium triacetoxyborohydride (14 mg, 0.069 mmol) and the resulting
solution was stirred at 60.degree. C. overnight. The reaction
mixture was diluted with MeOH and purified via preparative HPLC on
a C-18 column (pH 2, 12-30% MeCN/0.1% TFA (aq) over 12 min, 60
mL/min) to afford the title compound. LCMS for
C.sub.25H.sub.30N.sub.8O.sub.2S (M+H).sup.+: calculated m/z=507.6;
found 507.2.
Example 523.
3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methyl-N-(3-methyl-3-azabi-
cyclo[3.1.1]heptan-1-yl)benzenesulfonamide Trifluoroacetate
##STR00824##
[1566] Step 1.
3-((benzyloxy)carbonyl)-3-azabicyclo[3.1.I]heptane-1-carboxylic
Acid
##STR00825##
[1568] To a solution of 3-azabicyclo[3.1.1]heptane-1-carboxylic
acid (0.522 g, 3.70 mmol) and N-(benzyloxycarbonyloxy)succinimide
(1.01 g, 4.07 mmol) in DCM (15 mL) was added DIEA (0.97 mL, 5.6
mmol) and the resulting solution was stirred at ambient temperature
overnight. The reaction mixture was diluted with dichloromethane
(50 mL) and acidified by the addition of 1 N HCl (aq) (10 mL). The
layers were separated and the organic layer was washed with
H.sub.2O (3.times.5 mL) and the combined aqueous phases were
extracted with dichloromethane (10 mL). The combined organic layers
were washed with brine (10 mL), dried over Na.sub.2SO.sub.4,
filtered, and concentrated in-vacuo to afford an off-white solid
(1.00 g, 98%). LCMS for C.sub.15H.sub.17NO.sub.4 (M+H).sup.+:
calculated m/z=276.3; found 276.1.
Step 2. Benzyl
1-((tert-butoxycarbonyl)amino)-3-azabicyclo[3.1.I]heptane-3-carboxylate
##STR00826##
[1570] To a solution of
3-((benzyloxy)carbonyl)-3-azabicyclo[3.1.1]heptane-1-carboxylic
acid (150 mg, 0.545 mmol) and triethylamine (0.091 mL, 0.65 mmol)
in tert-butanol (3.0 mL) was added diphenyl phosphoryl azide (0.129
mL, 0.599 mmol) and the solution was heated at 85.degree. C. in a
sealed vial overnight. LCMS data indicated that the major reaction
component was the desired product. The crude reaction mixture was
concentrated in-vacuo and the residue was purified by CombiFlash
chromatography (25 g column, eluting with 0-50% ethyl
acetate/hexanes) to afford the desired product (45 mg, 24%). LCMS
for C.sub.19H.sub.26N.sub.2O.sub.4 (M+Na).sup.+: calculated
m/z=369.4; found 369.1.
Step 3. Benzyl 1-amino-3-azabicyclo[3.1.I]heptane-3-carboxylate
Hydrochloride
##STR00827##
[1572] To a solution of benzyl
1-((tert-butoxycarbonyl)amino)-3-azabicyclo[3.1.1]heptane-3-carboxylate
(45 mg, 0.130 mmol) in THF (1 mL) was added 4 N HCl in 1,4-dioxane
(2 mL, 8.00 mmol) and the solution was stirred at ambient
temperature for 2 h. The volatiles were removed in-vacuo and the
residue was placed under high vacuum prior to using in the
subsequent reaction. LCMS for
C.sub.14H.sub.18N.sub.2O.sub.2(M+H).sup.+: calculated m/z=247.3;
found 247.2.
Step 4. Benzyl
1-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonami-
do)-3-azabicyclo[3.1.I]heptane-3-carboxylate
##STR00828##
[1574] To a solution of benzyl
1-amino-3-azabicyclo[3.1.1]heptane-3-carboxylate hydrochloride (34
mg, 0.12 mmol), Et.sub.3N (0.069 mL, 0.49 mmol), and DMAP (1.5 mg,
0.012 mmol) in DCM (0.5 mL) was added
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylbenzenesulfonyl
chloride (40. mg, 0.12 mmol) and the resulting mixture was stirred
at ambient temperature overnight. The crude reaction mixture was
purified by CombiFlash chromatography (12 g silica gel column,
eluting with 0-15% methanol/dichloromethane) to afford the desired
product (18 mg, 27%). LCMS for C.sub.26H.sub.27N.sub.7O.sub.4S
(M+H).sup.+: calculated m/z=534.6; found 534.1.
Step 5.
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(3-azabicyclo[3.1.I-
]heptan-1-yl)-4-methylbenzenesulfonamide
##STR00829##
[1576] A mixture of benzyl
1-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonami-
do)-3-azabicyclo[3.1.1]heptane-3-carboxylate (18 mg, 0.034 mmol)
and 10% palladium (dry basis) on activated carbon, wet, Degussa
type E101 NE/W (4 mg) in MeOH (3 mL) was stirred for 16 h under an
atmosphere of hydrogen. The crude reaction mixture was purged with
nitrogen, diluted with EtOAc (20 mL), and filtered through a pad of
celite. The inorganics were washed thoroughly with EtOAc. The
volatiles were removed in-vacuo and the crude product was used in
the subsequent step without further purification. LCMS for
C.sub.18H.sub.21N.sub.7O.sub.2S (M+H).sup.+: calculated m/z=400.5;
found 400.1.
Step 6.
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methyl-N-(3-methyl--
3-azabicyclo[3.1.I]heptan-1-yl)benzenesulfonamide
Trifluoroacetate
[1577] A mixture of
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(3-azabicyclo[3.1.1]heptan-
-1-yl)-4-methylbenzenesulfonamide (14 mg, 0.035 mmol),
paraformaldehyde (2.1 mg, 0.070 mmol), and sodium
triacetoxyborohydride (15 mg, 0.070 mmol) in DCE (0.6 mL) was
stirred at ambient temperature for 4 h. The reaction mixture was
diluted with MeOH and purified via preparative HPLC on a C-18
column (pH 2, 5-23% MeCN/0.1% TFA (aq) over 12 min, 60 mL/min) to
afford the title compound. LCMS for C.sub.19H.sub.23N.sub.7O.sub.2S
(M+H).sup.+: calculated m/z=414.5; found 414.2.
Example 524.
3-(4-Amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-N-(3-iso-
propyl-3-azabicyclo[3.1.1]heptan-1-yl)-4-methylbenzenesulfonamide
Trifluoroacetate
##STR00830##
[1578] Step 1. Tert-Butyl
(3-azabicyclo[3.1.I]heptan-1-yl)carbamate
##STR00831##
[1580] A mixture of benzyl
1-((tert-butoxycarbonyl)amino)-3-azabicyclo[3.1.1]heptane-3-carboxylate
(236 mg, 0.681 mmol, prepared in Example 523, Step 2) and palladium
hydroxide 20% (dry basis), wet (24 mg, 0.034 mmol) in MeOH (5 mL)
was stirred under an atmosphere of H.sub.2 (g) while stirring at
ambient temperature. The crude reaction mixture was purged with
nitrogen, diluted with EtOAc (20 mL), and filtered through a pad of
celite. The inorganics were washed thoroughly with EtOAc. The
volatiles were removed in-vacuo and the crude product was used in
the subsequent step without further purification. LCMS for
C.sub.11H.sub.20N.sub.2O.sub.2 (M+H).sup.+: calculated m/z=213.3;
found 213.2.
Step 2. 3-isopropyl-3-azabicyclo[3.1.I]heptan-1-amine
Hydrochloride
##STR00832##
[1582] A mixture of tert-butyl
(3-azabicyclo[3.1.1]heptan-1-yl)carbamate (25 mg, 0.12 mmol),
acetone (0.043 mL, 0.59 mmol), and sodium triacetoxyborohydride
(42. mg, 0.20 mmol) in DCE (0.5 mL) was stirred at ambient
temperature overnight. 4 N HCl in 1,4-dioxane (1 mL) was added and
the resultant solution was stirred at ambient temperature for 5 h.
The volatiles were removed in-vacuo and the residue was
azeotropically washed with acetonitrile prior to placing it under
high vacuum. The crude product was used in the subsequent reaction
without further purification. LCMS for C.sub.9H.sub.18N.sub.2
(M+H).sup.+: calculated m/z=155.3; found 155.1.
Step 3.
3-(4-amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-N-
-(3-isopropyl-3-azabicyclo[3.1.1]heptan-1-yl)-4-methylbenzenesulfonamide
Trifluoroacetate
[1583] To a solution of
3-isopropyl-3-azabicyclo[3.1.1]heptan-1-amine hydrochloride (12 mg,
0.064 mmol) and
3-(4-amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-4-methyl-
benzenesulfonyl chloride (10. mg, 0.026 mmol) in DCM (0.5 mL) was
added sequentially Et.sub.3N (0.014 mL, 0.10 mmol), and DMAP (1.5
mg, 0.012 mmol). After 15 min. NMP (0.2 mL) was added and the
resulting solution was stirred at ambient temperature overnight.
The reaction mixture was quenched by the addition of 4 N HCl (aq)
(0.5 mL), diluted with MeOH, and purified via preparative HPLC on a
C-18 column (pH 2, 17-35% MeCN/0.1% TFA (aq) over 12 min, 60
mL/min) to afford the title compound. LCMS for
C.sub.22H.sub.26F.sub.3N.sub.7O.sub.2S (M+H).sup.+: calculated
m/z=510.6; found 510.2.
Example 525.
3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(3-cyclobutyl-3-azabicyclo-
[3.1.1]heptan-1-yl)-4-methylbenzenesulfonamide Trifluoroacetate
##STR00833##
[1585] To a solution of
3-cyclobutyl-3-azabicyclo[3.1.1]heptan-1-amine hydrochloride (13
mg, 0.064 mmol, prepared by using a procedure analogous to that in
Example 524, Steps 1-2) in DCE (1 mL) was added sequentially 1 N
Na.sub.2CO.sub.3 (aq) (1 mL) and
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylbenzenesulfonyl
chloride (8. mg, 0.03 mmol) and the resulting mixture was stirred
at ambient temperature overnight. The reaction mixture was quenched
by the addition of 4 N HCl (aq) (0.5 mL), diluted with MeOH, and
purified via preparative HPLC on a C-18 column (pH 2, 14-34%
MeCN/0.1% TFA (aq) over 5 min, 60 mL/min) to afford the title
compound. LCMS for C.sub.22H.sub.27N.sub.7O.sub.2S (M+H).sup.+:
calculated m/z=454.6; found 454.3.
Example 526.
3-(4-Amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-N-(1,3-d-
imethylpiperidin-3-yl)-4-methylbenzenesulfonamide
Trifluoroacetate
##STR00834##
[1586] Step 1. 1,3-dimethylpiperidin-3-amine Hydrochloride
##STR00835##
[1588] A mixture of tert-butyl (3-methylpiperidin-3-yl) carbamate
(50. mg, 0.23 mmol), paraformaldehyde (35 mg, 1.2 mmol), and sodium
triacetoxyborohydride (84 mg, 0.40 mmol) in DCE (1.0 mL) was
stirred at ambient temperature overnight. 4 N HCl in 1,4-dioxane (1
mL) was added and the resultant solution was stirred at ambient
temperature for 5 h. The volatiles were removed in-vacuo and the
residue was azeotropically washed with acetonitrile prior to
placing it under high vacuum. The crude product was used in the
subsequent reaction without further purification. LCMS for
C.sub.7H.sub.16N.sub.2(M+H).sup.+: calculated m/z=129.2; found
129.1.
Step 2.
3-(4-amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-N-
-(1,3-dimethylpiperidin-3-yl)-4-methylbenzenesulfonamide
trifluoroacetate
##STR00836##
[1590] To a solution of 1,3-dimethylpiperidin-3-amine hydrochloride
(10. mg, 0.064 mmol) in DCE (1 mL) was added sequentially 1 N
Na.sub.2CO.sub.3 (aq) (1 mL) and
3-(4-amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-4-methyl-
benzenesulfonyl chloride (10. mg, 0.026 mmol) and the resulting
mixture was stirred at ambient temperature overnight. The reaction
mixture was quenched by the addition of 4 N HCl (aq) (0.5 mL),
diluted with MeOH, and purified via preparative HPLC on a C-18
column (pH 2, 8-26% MeCN/0.1% TFA (aq) over 12 min, 60 mL/min) to
afford the title compound. LCMS for
C.sub.20H.sub.24F.sub.3N.sub.7O.sub.2S (M+H).sup.+: calculated
m/z=484.5; found 484.2.
Example 527.
3-(4-Amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-N-(1-iso-
propyl-3-methylpiperidin-3-yl)-4-methylbenzenesulfonamide
Trifluoroacetate
##STR00837##
[1592] A procedure analogous to that outlined in Example 526 was
used with the exception that 1-isopropyl-3-methylpiperidin-3-amine
hydrochloride (12 mg, 0.064 mmol) was used as the amine. LCMS for
C.sub.22H.sub.28F.sub.3N.sub.7O.sub.2S (M+H).sup.+: calculated
m/z=512.6; found 512.3.
Example 528.
3-(4-Amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-N-(1,4-d-
imethylpiperidin-4-yl)-4-methylbenzenesulfonamide
Trifluoroacetate
##STR00838##
[1594] To a vial containing
3-(4-amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-4-methyl-
benzenesulfonyl chloride (10 mg, 0.026 mmol) and DMAP (2.0 mg,
0.016 mmol) was added a solution of 1,4-dimethylpiperidin-4-amine
hydrochloride (9.2 mg, 0.056 mmol, prepared in a manner similar to
that outlined in Example 526, step 1) and Et.sub.3N (0.014 mL, 0.10
mmol) in DCM (0.6 mL) and NMP (0.4 mL) and the resulting mixture
was stirred at ambient temperature overnight. A second aliquot of
sulfonyl chloride was added and stirring was continued overnight.
The reaction was diluted with methanol (4 mL), acidified by the
addition of 4 N HCl (aq) (0.5 mL), syringe filtered, and purified
via preparative HPLC on a C-18 column (pH 2, 16-34% MeCN/0.1% TFA
(aq) over 12 min, 60 mL/min) to afford the title compound. LCMS for
C.sub.20H.sub.24F.sub.3N.sub.7O.sub.2S (M+H): calculated m/z=484.5;
found 484.2.
Example 529.
3-(4-Amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-N-(1-(3--
cyanocyclobutyl)-4-methylpiperidin-4-yl)-4-methylbenzenesulfonamide
Trifluoroacetate
##STR00839##
[1596] A procedure analogous to that outlined in Example 528 was
used with the exception that
3-(4-amino-4-methylpiperidin-1-yl)cyclobutane-1-carbonitrile
hydrochloride (13 mg, 0.056 mmol) was used as the amine. LCMS for
C.sub.24H.sub.27F.sub.3N.sub.8O.sub.2S (M+H).sup.+: calculated
m/z=549.6; found 549.1.
Example 530.
3-(4-Amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-4-methyl-
-N-(4-methyl-1-(tetrahydrofuran-3-yl)piperidin-4-yl)benzenesulfonamide
Trifluoroacetate
##STR00840##
[1598] A procedure analogous to that outlined in Example 528 was
used with the exception that
4-methyl-1-(tetrahydrofuran-3-yl)piperidin-4-amine hydrochloride
(12 mg, 0.056 mmol) was used as the amine. LCMS for
C.sub.23H.sub.28F.sub.3N.sub.7O.sub.3S (M+H)f: calculated
m/z=540.6; found 540.1.
Example 531.
3-(4-Amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-4-methyl-
-N-(3-methylazetidin-3-yl)benzenesulfonamide Trifluoroacetate
##STR00841##
[1599] Step 1. Benzyl
3-((tert-butoxycarbonyl)amino)-3-methylazetidine-1-carboxylate
##STR00842##
[1601] To a 0.degree. C. solution of tert-butyl
(3-methylazetidin-3-yl) carbamate (200 mg, 1.074 mmol) and
Et.sub.3N (0.299 mL, 2.15 mmol) in DCM (6 mL) was added benzyl
chloroformate (0.18 mL, 1.3 mmol) drop-wise. The solution was
allowed to gradually warm to ambient temperature while stirring for
3 h. The crude reaction mixture was purified by CombiFlash
chromatography (25 g silica gel column, eluting with 0-15%
methanol/dichloromethane) to afford the desired product (183 mg,
53%). LCMS for C.sub.17H.sub.24N.sub.2O.sub.4 (M+Na).sup.+:
calculated m/z=343.4; found 343.1.
Step 2. Benzyl 3-amino-3-methylazetidine-1-carboxylate
Trifluoroacetate
##STR00843##
[1603] Benzyl
3-((tert-butoxycarbonyl)amino)-3-methylazetidine-1-carboxylate (56
mg, 0.18 mmol) was dissolved in DCM (1 mL) and to this was added
TFA (1 mL) and the resulting solution was stirred at ambient
temperature for 4 h. The volatiles were removed in-vacuo and the
crude product was azeotropically washed with acetonitrile and
placed under high vacuum prior to use in the subsequent reaction.
LCMS for C.sub.12H.sub.16N.sub.2O.sub.2 (M+H).sup.+: calculated
m/z=221.3; found 221.1.
Step 3.
3-(4-amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-4-
-methyl-N-(3-methylazetidin-3-yl)benzenesulfonamide
Trifluoroacetate
[1604] A procedure analogous to that outlined in Example 523 steps
4-5 was used with the exception that benzyl
3-amino-3-methylazetidine-1-carboxylate trifluoroacetate (33 mg,
0.130 mmol) was used as the amine. LCMS for
C.sub.17H.sub.18F.sub.3N.sub.7O.sub.2S (M+H).sup.+: calculated
m/z=442.4; found 442.2.
Example 532.
3-(4-Amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-N-(1,3-d-
imethylazetidin-3-yl)-4-methylbenzenesulfonamide
##STR00844##
[1606] A procedure analogous to that outlined in Example 523 step 6
was used with the exception that
3-(4-amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-4-methyl-
-N-(3-methylazetidin-3-yl)benzenesulfonamide (18 mg, 0.041 mmol)
was used as the amine. The reaction mixture was diluted with MeOH
and purified via preparative HPLC on a C-18 column (pH 10, 20-38%
MeCN/NH.sub.4OH (aq) over 12 min, 60 mL/min) to afford the title
compound. LCMS for C.sub.18H.sub.20F.sub.3N.sub.7O.sub.2S
(M+H).sup.+: calculated m/z=456.5; found 456.1.
Example 533.
3-(4-Amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-N-(1,3-d-
imethylpyrrolidin-3-yl)-4-methylbenzenesulfonamide
Trifluoroacetate
##STR00845##
[1608] A procedure analogous to that outlined in Example 526 steps
1-2 was used with the exception that tert-butyl
(3-methylpyrrolidin-3-yl)carbamate was used as the starting amine.
LCMS for C.sub.19H.sub.22F.sub.3N.sub.7O.sub.2S (M+H).sup.+:
calculated m/z=470.5; found 470.2.
Example 534.
3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanocuban-1-yl)-4-meth-
ylbenzenesulfonamide Trifluoroacetate
##STR00846##
[1609] Step 1. Methyl-4-aminocubane-1-carboxylate Hydrochloride
##STR00847##
[1611] To a solution of
methyl-4-((tert-butoxycarbonyl)amino)cubane-1-carboxylate (150 mg,
0.541 mmol) in THF (2.0 mL) was added 4 N HCl in 1,4-dioxane (2.0
mL, 8.0 mmol) and the solution was stirred at ambient temperature
overnight. The volatiles were removed in-vacuo and the residue was
placed under high vacuum prior to using in the subsequent reaction.
LCMS for C.sub.10H.sub.11NO.sub.2 (M+H).sup.+: calculated
m/z=178.2; found 178.1.
Step 2. methyl
4-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonami-
do)cubane-1-carboxylate
##STR00848##
[1613] To a solution of methyl-4-aminocubane-1-carboxylate (96 mg,
0.54 mmol), Et.sub.3N (0.30 mL, 2.2 mmol), and DMAP (6.6 mg, 0.054
mmol) in DCM (0.5 mL) was added
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylbenzenesulfonyl
chloride (175 mg, 0.541 mmol) and the resulting solution was
stirred at ambient temperature for 6 h. The crude reaction mixture
was purified by CombiFlash chromatography (25 g silica gel column,
eluting with 0-15% methanol/dichloromethane) to afford the desired
product (93 mg, 38%). LCMS for C.sub.22H.sub.20N.sub.6O.sub.4S
(M+H).sup.+: calculated m/z=465.5; found 465.2.
Step 3.
4-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)su-
lfonamido)cubane-1-carboxamide
##STR00849##
[1615] A solution of methyl
4-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonami-
do)cubane-1-carboxylate (20 mg, 0.043 mmol) in ammonia in methanol
7 N (1.0 mL, 7.0 mmol) was stirred at ambient temperature
overnight. The volatiles were removed in-vacuo and the crude
product was used in the subsequent reaction without further
purification. LCMS for C.sub.21H.sub.19N.sub.7O.sub.3S (M+H).sup.+:
calculated m/z=450.5; found 450.2.
Step 4.
3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-cyanocuban-1-yl)-
-4-methylbenzenesulfonamide Trifluoroacetate
##STR00850##
[1617]
4-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sul-
fonamido)cubane-1-carboxamide formed above was dissolved in
anhydrous DCM (1.0 mL) and to this was added sequentially Et.sub.3N
(0.024 mL, 0.17 mmol) and trifluoroacetic anhydride (7.0 .mu.L,
0.050 mmol) and the resulting solution was stirred at ambient
temperature. After 2 h, a second aliquot of Et.sub.3N and TFAA were
added and stirring was continued for an additional 2 h. The
reaction mixture was diluted with MeOH and purified via preparative
HPLC on a C-18 column (pH 2, eluting with MeCN/0.1% TFA (aq)). LCMS
for C.sub.21H.sub.17N.sub.7O.sub.2S (M+H).sup.+: calculated
m/z=432.5; found 432.1.
Example 535.
3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-N-(4-(2-hydroxypropan-2-yl)c-
uban-1-yl)-4-methylbenzenesulfonamide Trifluoroacetate
##STR00851##
[1619] To a solution of methyl
4-((3-(4-aminoimidazo[2,1-][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonamid-
o)cubane-1-carboxylate (20 mg, 0.043 mmol) in anhydrous THF (1.0
mL) was added 3 M methylmagnesium bromide in ether (0.072 mL, 0.22
mmol) and the resulting solution was stirred at ambient temperature
overnight. The reaction mixture was diluted with MeOH and purified
via preparative HPLC on a C-18 column (pH 2, 16-34% MeCN/0.1% TFA
(aq) over 12 min, 60 mL/min) afforded the title compound. LCMS for
C.sub.23H.sub.24N.sub.6O.sub.3S (M+H).sup.+: calculated m/z=465.5;
found 465.3.
Example 536.
3-(2-Methyl-5-(methylsulfonyl)phenyl)-6-(tetrahydro-2H-pyran-4-yl)imidazo-
[1,2-a]pyrazin-8-amine Trifluoroacetate
##STR00852##
[1620] Step 1.
6-(3,6-dihydro-2H-pyran-4-yl)-3-(2-methyl-5-(methylsulfonyl)phenyl)imidaz-
o[1,2-a]pyrazin-8-amine
##STR00853##
[1622] A mixture of
2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(28 mg, 0.13 mmol),
6-bromo-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-8-amin-
e (25 mg, 0.065 mmol), Pd(Ph.sub.3P).sub.4 (7.5 mg, 0.006 mmol),
and K.sub.2CO.sub.3 (27 mg, 0.20 mmol) in 1,4-dioxane (1.0 mL) was
de-gassed and purged with nitrogen several times prior to heating
at 110.degree. C. in a sealed vial overnight. The crude reaction
mixture was diluted with EtOAc (20 mL) and filtered through a pad
of celite. The inorganics were washed thoroughly with EtOAc. The
volatiles were removed in-vacuo and the crude product was purified
by CombiFlash chromatography (12 g silica gel column, eluting with
0-20% methanol/dichloromethane) to afford the desired product (11
mg, 44%). LCMS for C.sub.19H.sub.20N.sub.4O.sub.3S (M+H).sup.+:
calculated m/z=385.5; found 385.2.
Step 2.
3-(2-Methyl-5-(methylsulfonyl)phenyl)-6-(tetrahydro-2H-pyran-4-yl)-
imidazo[1,2-a]pyrazin-8-amine Trifluoroacetate
[1623] A mixture of
6-(3,6-dihydro-2H-pyran-4-yl)-3-(2-methyl-5-(methylsulfonyl)phenyl)imidaz-
o[1,2-a]pyrazin-8-amine (5.5 mg, 0.014 mmol) and palladium
hydroxide (2.0 mg, 2.9 .mu.mol) in MeOH (2 mL) and THF (1 mL) was
stirred under an atmosphere of H.sub.2 (g) via a balloon. The crude
reaction mixture was purged with nitrogen, diluted with EtOAc (10
mL), and filtered through a pad of celite. The inorganics were
washed thoroughly with EtOAc. The volatiles were removed in-vacuo
and the crude product was diluted with MeOH and purified via
preparative HPLC on a C-18 column (pH 2, 13-33% MeCN/0.1% TFA (aq)
over 5 min, 60 mL/min) to afford the title compound. LCMS for
C.sub.19H.sub.22N.sub.4O.sub.3S (M+H).sup.+: calculated m/z=387.5;
found 387.1.
Example 537.
1-(4-(8-Amino-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin--
6-yl)piperidin-1-yl)ethan-1-one Trifluoroacetate
##STR00854##
[1624] Step 1.
3-(2-methyl-5-(methylsulfonyl)phenyl)-6-(piperidin-4-yl)imidazo[1,2-a]pyr-
azin-8-amine
##STR00855##
[1626] A procedure analogous to that outlined in Example 536, steps
1-2 was used with the exception that benzyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-
-carboxylate (90 mg, 0.26 mmol) was used as the starting boronic
ester. LCMS for C.sub.19H.sub.23N.sub.5O.sub.2S (M+H).sup.+:
calculated m/z=386.5; found 386.2.
Step 2.
1-(4-(8-amino-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]p-
yrazin-6-yl)piperidin-1-yl)ethan-1-one Trifluoroacetate
[1627] To a 0.degree. C. solution of
3-(2-methyl-5-(methylsulfonyl)phenyl)-6-(piperidin-4-yl)imidazo[1,2-a]pyr-
azin-8-amine (15 mg, 0.039 mmol) in DCM (1 mL) was added a solution
of acetyl chloride (3.0 .mu.L, 0.043 mmol) in DCM (0.5 mL) and the
resulting solution was allowed to gradually warm to ambient
temperature overnight. The reaction mixture was diluted with MeOH
and purified via preparative HPLC on a C-18 column (pH 2, 11-31%
MeCN/0.1% TFA (aq) over 5 min, 60 mL/min) to afford the title
compound. LCMS for C.sub.21H.sub.25N.sub.5O.sub.3S (M+H).sup.+:
calculated m/z=428.5; found 428.2.
Example 538. Methyl
3-(8-amino-3-(2-methyl-5-(methylsulfonyl)phenyl)imidazo[1,2-a]pyrazin-6-y-
l)pyrrolidine-1-carboxylate Trifluoroacetate
##STR00856##
[1629] A procedure analogous to that outlined in Example 537 steps
1-2 was used with the exception that tert-butyl
3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1--
carboxylate (77 mg, 0.26 mmol) was used as the starting boronic
ester in step 1 and methyl chloroformate was used as the acylating
reagent in step 2. LCMS for C.sub.20H.sub.23N.sub.5O.sub.4S
(M+H).sup.+: calculated m/z=430.5; found 430.1.
Example 539.
5-((3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonami-
do)-N-(2,2,2-trifluoroethyl)picolinamide Trifluoroacetate
##STR00857##
[1631] To a solution of 2,2,2-trifluoroethylamine (0.015 mL, 0.19
mmol) in anhydrous DCM (0.5 mL) was added 2.0 M trimethylaluminum
in toluene (0.10 mL, 0.20 mmol) and the resulting solution was
stirred at ambient temperature for 30 min. This solution was added
via syringe to a cloudy solution of methyl
5-((3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)sulfonami-
do)picolinate (14 mg, 0.032 mmol) in anhydrous DCM (0.5 mL). The
resulting mixture was stirred overnight. The crude reaction mixture
was diluted with DCM (10 mL) and quenched by the careful addition
of MeOH followed by saturated NH.sub.4Cl (aq) and the resulting
slurry was stirred for 10 min. The crude reaction mixture was
filtered through a pad of celite and the inorganics were washed
thoroughly with DCM. The volatiles were removed in-vacuo and the
crude product was diluted with MeOH and purified via preparative
HPLC on a C-18 column (pH 2, 23-41% MeCN/0.1% TFA (aq) over 12 min,
60 mL/min) to afford the title compound. LCMS for
C.sub.20H.sub.17F.sub.3N.sub.8O.sub.3S (M+H).sup.+: calculated
m/z=507.5; found 507.2.
Example A. THP-1 RPS6 ELISA Assay
[1632] To measure the Phosphorylated Ribosomal Protein S6 (RPS6) in
cell lysates, THP-1 cells (Human Acute Monocytic Leukemia) are
purchased from ATCC (Manassas, Va.) and maintained in RPMI with 10%
FBS (Gibco/Life Technologies, Carlsbad, Calif.). For the assay,
THP-1 cells are serum starved overnight in RPMI, then plated in
RPMI (2.times.10.sup.5 cells/well in 90 .mu.L) into 96-well
flat-bottom tissue culture treated plates (Corning, Corning, N.Y.),
in the presence or absence of a concentration range of test
compounds. Covered plates are incubated for 2 hours at 37.degree.
C., 5% CO.sub.2 then treated with or without 10 nM
MCP-1(MYBioSource, San Diego, Calif.) for 15 minutes at 37.degree.
C., 5% CO.sub.2. Plates are centrifuged at 1600 RPM and
supernatants are removed. Cells are lysed in Lysis Buffer (Cell
Signaling, Danvers, Mass.) with Protease Inhibitor (Calbiochem/EMD,
Germany), PMSF (Sigma, St Louis Mo.), HALTS (Thermo Fisher,
Rockford, Ill.) for 30 min on wet ice. Cell lysates are frozen at
-80.degree. C. before testing. The lysates are tested in the
Human/Mouse/Rat Phospho-RPS6 ELISA (R&D Systems, Inc. Minn,
Minn.). The plate is measured using a microplate reader (SpectraMax
M5-Molecular Devices, LLC Sunnyvale, Calif.) set to 450 nm with a
wavelength correction of 540. IC.sub.50 determination is performed
by fitting the curve of inhibitor percent inhibition versus the log
of the inhibitor concentration using the GraphPad Prism 5.0
software.
Example B. PI3K-.gamma. Scintillation Proximity Assay
[1633] Materials
[1634] [.gamma.-.sup.33P]ATP (10 mCi/mL) and Wheat Germ Agglutinin
(WGA) YSi SPA Scintillation Beads was purchased from Perkin-Elmer
(Waltham, Mass.). Lipid kinase substrate,
D-myo-Phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2)D
(+)-sn-1,2-di-O-octanoylglyceryl, 3-O-phospho linked (PIP2), CAS
204858-53-7, was purchased from Echelon Biosciences (Salt Lake
City, Utah). PI3K.gamma. (p110.gamma.) Recombinant Human Protein
was purchased from Life technology (Grand Island, N.Y.). ATP,
MgCl.sub.2, DTT, EDTA, MOPS and CHAPS were purchased from
Sigma-Aldrich (St. Louis, Mo.).
[1635] The kinase reaction was conducted in polystyrene 384-well
Greiner Bio-one white plate from Thermo Fisher Scientific in a
final volume of 25 .mu.L. Inhibitors were first diluted serially in
DMSO and added to the plate wells before the addition of other
reaction components. The final concentration of DMSO in the assay
was 2%. The PI3K.gamma. assay was carried out at room temperature
in 20 mM MOPS, pH 6.7, 10 mM MgCl.sub.2, 5 mM DTT and CHAPS 0.03%.
Reactions were initiated by the addition of ATP, the final reaction
mixture consisted of M PIP2, 2 .mu.M ATP, 0.5 .mu.Ci
[.gamma.-.sup.33P] ATP, 13 nM PI3K.gamma.. Reactions were incubated
for 120 min and terminated by the addition of 40 .mu.L SPA beads
suspended in quench buffer: 163 mM potassium phosphate pH 7.8, 20%
glycerol, 25 mM EDTA. The final concentration of SPA beads is 1.0
mg/mL. After the plate sealing, plates were shaken overnight at
room temperature and centrifuged at 1500 rpm for 10 min, the
radioactivity of the product was determined by scintillation
counting on Topcount (Perkin-Elmer). IC.sub.50 determination was
performed by fitting the curve of percent of the solvent control
activity versus the log of the inhibitor concentration using the
GraphPad Prism 6.0 software. Data for the Examples, obtained using
the methods described in Example B, are provided in Table 22.
Example C. PI3K.delta. Scintillation Proximity Assay
[1636] Materials
[1637] [.gamma.-.sup.33P]ATP (10 mCi/mL) and Wheat Germ Agglutinin
(WGA) YSi SPA Scintillation Beads was purchased from Perkin-Elmer
(Waltham, Mass.). Lipid kinase substrate,
D-myo-Phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2)D
(+)-sn-1,2-di-O-octanoylglyceryl, 3-O-phospho linked (PIP2), CAS
204858-53-7, was purchased from Echelon Biosciences (Salt Lake
City, Utah). PI3K.delta. (p1106/p85a) Recombinant Human Protein was
purchased from Eurofins (St Charles, Mo.). ATP, MgCl.sub.2, DTT,
EDTA, MOPS and CHAPS were purchased from Sigma-Aldrich (St. Louis,
Mo.).
[1638] The kinase reaction was conducted in polystyrene 384-well
Greiner Bio-one white plate from Thermo Fisher Scientific in a
final volume of 25 .mu.L. Inhibitors were first diluted serially in
DMSO and added to the plate wells before the addition of other
reaction components. The final concentration of DMSO in the assay
was 2%. The PI3K.delta. assay was carried out at room temperature
in 20 mM MOPS, pH 6.7, 10 mM MgCl.sub.2, 5 mM DTT and CHAPS 0.0300.
Reactions were initiated by the addition of ATP, the final reaction
mixture consisted of M PIP2, 2 .mu.M ATP, 0.5 .mu.Ci
[.gamma.-.sup.33P] ATP, 3.4 nM PI3K.delta.. Reactions were
incubated for 120 min and terminated by the addition of 40 .mu.L
SPA beads suspended in quench buffer: 163 mM potassium phosphate pH
7.8, 20% glycerol, 25 mM EDTA. The final concentration of SPA beads
is 1.0 mg/mL. After the plate sealing, plates were shaken overnight
at room temperature and centrifuged at 1500 rpm for 10 min, the
radioactivity of the product was determined by scintillation
counting on Topcount (Perkin-Elmer). IC.sub.50 determination was
performed by fitting the curve of percent of the solvent control
activity versus the log of the inhibitor concentration using the
GraphPad Prism 6.0 software.
[1639] Data for the Examples, obtained using the methods described
in Examples A, B and C, are provided in Table 22.
TABLE-US-00026 TABLE 22 PI3K.gamma. PI3K.delta.
PI3K.gamma._THP1_RPS6_ELISA Ex. No. IC.sub.50 (nM) IC.sub.50 (nM)
IC.sub.50 (nM) 1 ++ +++ #### 2 ++ +++ #### 3 ++ ++++ -- 4 + ++ # 5
+ ++ ## 6 +++ ++++ -- 7 ++ +++ -- 8 + ++ #### 9 + +++ #### 10 + ++
#### 11 + +++ # 12 + ++ ## 13 + ++ ## 14 + + #### 15 + +++ #### 16
+ + # 17 + ++ ## 18 + ++ # 19 + ++ # 20 + + # 21 + + # 22 + + # 23
+ + # 24 + + ## 25 + ++ ## 26 + + ## 27 + ++ # 28 + ++ ## 29 + ++
#### 30 + + # 31 + + #### 32 + + # 33 + ++ ### 34 + ++ ## 35 + ++ #
36 + + # 37 + + ## 38 + + # 39 + ++ ## 40 + ++ -- 41 + ++ #### 42 +
+++ ### 43 ++ + -- 44 +++ ++++ -- 45 + +++ -- 46 + ++ -- 47 + +++
#### 48 + +++ #### 49 + +++ #### 50 + +++ #### 51 + +++ #### 52 +
++ ### 53 + +++ #### 54 + ++ #### 55 + ++++ #### 56 + +++ #### 57 +
+++ #### 58 ++ +++ #### 59 + +++ #### 60 + ++ ## 61 + +++ ### 62 +
++ ## 63 + ++ ## 64 + ++++ #### 65 + ++++ #### 66 ++ ++++ -- 67 ++
++++ 68 + +++ ### 69 + +++ ## 70 + +++ #### 71 + ++++ ## 72 + ++++
#### 73 + +++ #### 74 + +++ #### 75 + + ## 76 + ++ ## 77 + ++ ## 78
+ ++ ### 79 + + ## 80 + ++ ## 81 + + # 82 + + # 83 ++ + #### 84 +
+++ #### 85 + +++ ## 86 + +++ #### 87 + ++ ## 88 + ++ # 89 + ++ #
90 + ++ # 91 + ++ ## 92 + ++ # 93 + ++ ## 94 + ++ ### 95 + ++ ## 96
+ ++ #### 97 + ++ ## 98 + +++ ## 99 + +++ #### 100 + +++ ### 101 +
+++ #### 102 + ++ ## 103 + +++ #### 104 + +++ ### 105 + +++ -- 106
+ +++ #### 107 + ++ ### 108 + ++ ## 109 + +++ #### 110 + ++ ####
111 + ++ ## 112 + ++ ## 113 + +++ ## 114 + ++ ## 115 + +++ ## 116 +
+++ ## 117 + +++ ## 118 + ++ #### 119 ++ ++++ -- 120 + ++ -- 121 ++
++++ #### 122 + +++ ## 123 + +++ ### 124 + ++ ## 125 + +++ #### 126
+ +++ ## 127 + +++ ## 128 + ++ ## 129 + ++ # 130 + +++ ### 131 ++
+++ #### 132 + ++ ## 133 + +++ #### 134 + +++ ## 135 + ++ #### 136
++ ++++ #### 137 + +++ #### 138 + +++ #### 139 + +++ #### 140 + +++
## 141 + ++ ## 142 + +++ ## 143 + ++ #### 144 + ++ ### 145 + ++ ##
146 + ++ -- 147 + ++ ## 148 ++ +++ -- 149 + ++ -- 150 + +++ -- 151
+ ++ -- 152 + +++ -- 153 + +++ -- 154 + ++++ -- 155 + ++ ## 156 +
+++ ### 157 + +++ ### 158 + +++ -- 159 ++ ++++ -- 160 ++ +++ -- 161
+ ++ -- 162 + +++ -- 163 + +++ -- 164 + +++ -- 165 + ++ ### 166 +
++ ## 167 ++ ++++ -- 168 + +++ -- 169 ++ ++++ -- 170 + +++ -- 171
++ +++ -- 172 ++ +++ -- 173 ++ ++++ -- 174 ++ ++++ -- 175 + ++ ##
176 ++ ++++ -- 177 + +++ -- 178 + +++ -- 179 + +++ -- 180 + ++ ##
181 + + ## 182 + +++ ### 183 + ++ # 184 + + # 185 + ++ ## 186 + ++
## 187 + ++ ## 188 + + ## 189 + +++ ### 190 + +++ #### 191 + +++ --
192 + ++ ### 193 + +++ -- 194 + +++ ## 195 + ++ -- 196 + +++ -- 197
+ +++ ### 198 ++ +++ -- 199 + +++ ### 200 + +++ -- 201 + +++ -- 202
++ +++ -- 203 + ++ ### 204 ++ +++ -- 205 + +++ #### 206 + +++ ####
207 + ++ -- 208 + +++ ### 209 + +++ -- 210 + ++ ## 211 + +++ ###
212 + +++ ### 213 + +++ -- 214 + - -- 215 + - -- 216 + - -- 217 + -
-- 218 + - -- 219 ++ - -- 220 + - -- 221 + - -- 222 + - -- 223 + -
-- 224 + - -- 225 + - -- 226 + - -- 227 + - -- 228 + - -- 229 + -
-- 230 + - -- 231 + - -- 232 + - -- 233 + - -- 234 ++ - -- 235 + -
-- 236 + - -- 237 + - -- 238 ++ - -- 239 +++ - -- 240 + - -- 241 +
- -- 242 + - -- 243 + - -- 244 + - --
245 + - -- 246 + - -- 247 + - -- 248 + - -- 249 + ++ ## 250 + ++ ##
251 + ++ # 252 + ++ ## 253 + ++ # 254 + ++ # 255 + ++ # 256 + ++ ##
257 + +++ #### 258 + ++ ### 259 + ++ # 260 + +++ -- 261 + +++ # 262
+ + ## 263 + ++ ## 264 + ++ ## 265 + + # 266 + ++ ## 267 + ++ ##
268 + ++ ## 269 + ++ ## 270 + ++ # 271 + ++ # 272 + ++ ## 273 + +++
## 274 + ++ # 275 + ++ ## 276 + ++ # 277 + ++ # 278 + ++ # 279 + +
# 280 + ++ ## 281 + ++ ## 282 + ++ # 283 + ++ ## 284 + ++ ## 285 +
++ ## 286 + ++ # 287 + ++ # 288 + ++ ## 289 + ++ ## 290 + +++ ####
291 + ++ ### 292 + +++ #### 293 + ++ ## 294 + +++ #### 295 + +++
#### 296 + +++ ## 297 + +++ -- 298 + +++ -- 299 + ++ ## 300 + +++
-- 301 + +++ ## 302 + +++ -- 303 + +++ -- 304 + +++ -- 305 + ++
#### 306 + + # 307 + + ## 308 + + # 309 + +++ ## 310 + ++ # 311 +
++ # 312 + ++ ## 313 + ++ -- 314 + ++ ## 315 + + # 316 + ++ # 317 +
++ # 318 + ++ # 319 + ++ # 320 + ++ ## 321 + + # 322 + ++ # 323 +
++ # 324 + ++ # 325 + + ## 326 + ++ # 327 + ++ ## 328 + ++ # 329 +
++ ## 330 + + # 331 + ++ ## 332 + ++ # 333 + ++ # 334 + ++ # 335 +
++ ## 336 + ++ ## 337 + ++ ## 338 + ++ ## 339 + ++ ## 340 + ++ ##
341 + ++ ## 342 + ++ ## 343 + + # 344 + + ## 345 + ++ #### 346 + ++
## 347 + ++ # 348 + + ## 349 + +++ -- 350 ++ +++ -- 351 + +++ --
352 + +++ -- 353 + +++ #### 354 + +++ #### 355 + ++ ## 356 + ++ #
357 + - -- 358 + - -- 359 + ++ #### 360 ++ ++ #### 361 ++ ++ -- 362
+ ++ # 363 + +++ ## 364 + ++ # 365 + ++ ## 366 + ++ -- 367 + ++
#### 368 + ++ -- 369 + ++ -- 370 + ++ # 371 + ++ ## 372 + +++ --
373 +++ +++ -- 374 + +++ ### 375 + ++ # 376 + ++ #### 377 + + # 378
+ ++ # 379 + ++ # 380 + +++ #### 381 + ++ ## 382 ++ +++ -- 383 + +
# 384 + + ### 385 + + ## 386 + ++ # 387 + ++ # 388 + ++ #### 389 +
+ # 390 + ++ ## 391 + ++ # 392 + + ## 393 + +++ ## 394 + ++ ## 395
+ ++ ## 396 + ++ ### 397 + ++ # 398 + ++ ### 399 + + #### 400 + + #
401 + ++++ -- 402 + ++ ## 403 + ++ # 404 + + # 405 + ++ # 406 + + #
407 +++ ++++ -- 408 + ++ #### 409 + ++ ## 410 + + # 411 + ++ ## 412
+ ++ # 413 + ++ # 414 + + ## 415 + ++ # 416 + ++ # 417 + ++ ### 418
+ ++ #### 419 + = #### 420 + ++ ## 421 + + # 422 + + # 423 + + #
424 + ++ ## 425 + ++ # 426 + ++ ## 427 + ++ ## 428 + ++ ## 429 + ++
## 430 + ++ ## 431 + ++ ## 432 + ++ ## 433 + ++ ## 434 + ++ ## 435
+ ++ ### 436 + ++ ## 437 + ++ ## 438 + ++ # 439 + +++ ### 440 + ++
## 441 + ++ ## 442 + +++ ## 443 + + ## 444 + + ## 445 + ++ ## 446 +
++ ## 447 + +++ ### 448 + +++ ## 449 + ++ #### 450 + ++ ### 451 +
++ ### 452 ++++ ++ -- 453 ++ ++ -- 454 ++ +++ -- 455 +++ +++ -- 456
++ ++ -- 457 ++ ++ -- 458 +++ ++++ -- 459 ++ ++++ -- 460 +++ ++++
-- 461 ++ +++ -- 462 + +++ -- 463 + ++ ## 464 + + # 465 + +++ ##
466 + + # 467 + ++ # 468 + ++ ## 469 + ++ ## 470 + +++ -- 471 ++
+++ #### 472 + ++ ## 473 + +++ -- 474 + ++ ## 475 + ++ ### 476 + ++
## 477 + ++ ## 478 ++ +++ -- 479 + ++ -- 480 + ++ -- 481 + ++ ##
482 + +++ #### 483 + + #### 484 + ++ ## 485 + ++ ## 486 + ++ ## 487
+ ++ -- 488 + ++ ## 489 + ++ ## 490 + ++ # 491 + ++ ## 492 + +++
### 493 ++ ++++ #### 494 + +++ #### 495 + +++ ####
496 + +++ ### 497 ++ +++ -- 498 + +++ -- 499 ++ +++ -- 500 + +++ ##
501 + +++ -- 502 + + ## 503 + + ## 504 + + # 505 + + ## 506 + + #
507 + ++ ### 508 + ++ ### 509 + +++ #### 510 + ++ #### 511 +++ ++++
-- 512 + ++++ -- 513 + ++ ## 514 ++ +++ -- 515 ++ ++++ -- 516 + + #
517 + +++ -- 518 ++ +++ ## 519 ++ + #### 520 + - -- 521 + - -- 522
+ - -- 523 + - -- 524 + - -- 525 ++ - -- 526 + - -- 527 + - -- 528
+ - -- 529 ++ - -- 530 ++ - -- 531 + - -- 532 + - -- 533 + - -- 534
+ - -- 535 + - -- 536 + - -- 537 + - -- 538 ++ - -- 539 + - -- +
refers to IC.sub.50 of .ltoreq.100 nM; ++ refers to IC.sub.50 of
.ltoreq.500 nM; +++ refers to an IC.sub.50 of <2000 nM; ++++
refers to an IC.sub.50 of .gtoreq.2000 nM. # refers to IC.sub.50 of
.ltoreq.100 nM; ## refers to IC.sub.50 of .ltoreq.500 nM; ###
refers to IC.sub.50 of <1000 nM; #### refers to an IC.sub.50 of
.gtoreq.1000 nM.
[1640] Various modifications of the invention, in addition to those
described herein, will be apparent to those skilled in the art from
the foregoing description. Such modifications are also intended to
fall within the scope of the appended claims. Each reference,
including all patent, patent applications, and publications, cited
in the present application is incorporated herein by reference in
its entirety.
* * * * *